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Journal articles on the topic 'Tubular epithelial cell'
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1
Oberley, T. D., A. H. Yang, and J. Gould-Kostka. "Selection of kidney cell types in primary glomerular explant outgrowths by in vitro culture conditions." Journal of Cell Science 84, no. 1 (August 1, 1986): 69–92. http://dx.doi.org/10.1242/jcs.84.1.69.
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Adult guinea pig glomeruli were grown in vitro either in serum or in a chemically defined medium. Glomeruli were plated either directly into plastic flasks or into plastic flasks that had been coated with the extracellular matrix produced by the PF-HR-9 mouse teratocarcinoma endodermal cell line. Both the composition of the medium and the nature of the culture substrate affected whole glomerular attachment and the type of cells produced in culture. Quantitative studies demonstrated selection of cell types by different culture conditions. Three colony types, each composed of distinctive cell types, could be identified by morphological features. The cells constituting two of these colony types were epithelial in nature, but they were identified as different epithelial types by both histochemical and ultrastructural criteria. Previous studies suggested that one epithelial cell type was derived from the glomerular visceral epithelial cell. This study demonstrates that this cell type could be selectively grown in defined medium on plastic. A second cell type showed several features of renal tubular epithelial cells, including histochemical staining for catalase, cell surface microvilli and cilia, and formation of hemicysts and structures that resembled tubules after prolonged periods in culture. To demonstrate that the ‘glomerulus-derived’ tubular cells were indeed tubular epithelium, we isolated purified renal cortical tubules (greater than 99% pure) and cultured them on the HR-9 matrix in a serum-free chemically defined medium. The resultant outgrowths had morphological properties identical to those of the glomerulus-derived tubular cells. It seems likely that small tubular fragments attached to a minority of the glomeruli are the source of these glomerulus-derived tubular cells. Neither epithelial cell type could be subcultured on plastic, but both could be passaged on the HR-9 matrix. A third cell type, the spindle-shaped cell, was easily propagated on both plastic and the HR-9 matrix. The origin of this cell type is not clear. Our results demonstrate the important effect of culture conditions on the selection, growth and differentiation of kidney cell types in vitro.
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Liu, Lele, Yuanjun Deng, Yang Cai, Pingfan Lu, Yiyan Guo, Chunjiang Zhang, Qian Li, Tianjing Zhang, Min Han, and Gang Xu. "Ablation of Gsa impairs renal tubule proliferation after injury via CDK2/cyclin E." American Journal of Physiology-Renal Physiology 318, no. 3 (March 1, 2020): F793—F803. http://dx.doi.org/10.1152/ajprenal.00367.2019.
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Acute kidney injury has a high global morbidity associated with an increased risk of death and chronic kidney disease. Renal tubular epithelial cell regeneration following injury may be a decisive factor in renal repair or the progression of acute kidney injury to chronic kidney disease, but the underlying mechanism of abnormal renal tubular repair remains unclear. In the present study, we investigated the role of heterotrimeric G stimulatory protein α-subunit (Gsa) in renal tubular epithelial cell regeneration. We generated renal tubule epithelium-specific Gsa knockout (GsaKspKO) mice to show the essential role of Gsa in renal tubular epithelial cell regeneration in two AKI models: acute aristolochic acid nephropathy (AAN) and unilateral ischemia-reperfusion injury (UIRI). GsaKspKO mice developed more severe renal impairment after AAN and UIRI, higher serum creatinine levels, and more substantial tubular necrosis than wild-type mice. More importantly, Gsa inactivation impaired renal tubular epithelial cell proliferation by reducing bromodeoxyuridine+ cell numbers in the AAN model and inhibiting cyclin-dependent kinase 2/cyclin E1 expression in the UIRI model. This reduced proliferation was further supported in vitro with Gsa-targeting siRNA. Downregulation of Gsa inhibited tubular epithelial cell proliferation in HK-2 and mIMCD-3 cells. Furthermore, Gsa downregulation inhibited cyclin-dependent kinase 2/cyclin E1 expression, which was dependent on the Raf-MEK-ERK signaling pathway. In conclusion, Gsa is required for tubular epithelial cell regeneration during kidney repair after AKI. Loss of Gsa impairs renal tubular epithelial cell regeneration by blocking the Raf-MEK-ERK pathway.
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Breda, Philippe Christophe, Thorsten Wiech, Catherine Meyer-Schwesinger, Florian Grahammer, Tobias Huber, Ulf Panzer, Gisa Tiegs, and Katrin Neumann. "Renal proximal tubular epithelial cells exert immunomodulatory function by driving inflammatory CD4+ T cell responses." American Journal of Physiology-Renal Physiology 317, no. 1 (July 1, 2019): F77—F89. http://dx.doi.org/10.1152/ajprenal.00427.2018.
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In immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN), inflammatory CD4+ T cells accumulate within the tubulointerstitial compartment in close contact to proximal and distal tubular epithelial cells and drive renal inflammation and tissue damage. However, whether renal epithelial cell populations play a role in the pathogenesis of cGN by modulating CD4+ T cell responses is less clear. In the present study, we aimed to investigate the potential of renal epithelial cells to function as antigen-presenting cells, thereby stimulating CD4+ T cell responses. Using a FACS-based protocol that allowed comparative analysis of cortical epithelial cell populations, we showed that particularly proximal tubular epithelial cells (PTECs) express molecules linked with antigen-presenting cell function, including major histocompatibility complex class II (MHCII), CD74, CD80, and CD86 in homeostasis and nephrotoxic nephritis, a murine model of cGN. Protein expression was visualized at the PTEC single cell level by imaging flow cytometry. Interestingly, we found inflammation-dependent regulation of epithelium-expressed CD74, CD80, and CD86, whereas MHCII expression was not altered. Antigen-specific stimulation of CD4+ T cells by PTECs in vitro supported CD4+ T cell survival and induced CD4+ T cell activation, proliferation, and inflammatory cytokine production. In patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis, MHCII and CD74 were expressed by both proximal and distal tubules, whereas CD86 was predominantly expressed by proximal tubules. Thus, particularly PTECs have the potential to induce an inflammatory phenotype in CD4+ T cells in vitro, which might also play a role in the pathology of immune-mediated kidney disease.
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TANG, Sydney, Kwok-Wah CHAN, Tak-Mao CHAN, and Kar-Neng LAI. "Sloughing renal tubular epithelial cell." Hong Kong Journal of Nephrology 4, no. 1 (April 2002): 61. http://dx.doi.org/10.1016/s1561-5413(09)60079-x.
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Carlisle, Rachel E., Alana Heffernan, Elise Brimble, Limin Liu, Danielle Jerome, Celeste A. Collins, Zahraa Mohammed-Ali, Peter J. Margetts, Richard C. Austin, and Jeffrey G. Dickhout. "TDAG51 mediates epithelial-to-mesenchymal transition in human proximal tubular epithelium." American Journal of Physiology-Renal Physiology 303, no. 3 (August 1, 2012): F467—F481. http://dx.doi.org/10.1152/ajprenal.00481.2011.
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Epithelial-to-mesenchymal transition (EMT) contributes to renal fibrosis in chronic kidney disease. Endoplasmic reticulum (ER) stress, a feature of many forms of kidney disease, results from the accumulation of misfolded proteins in the ER and leads to the unfolded protein response (UPR). We hypothesized that ER stress mediates EMT in human renal proximal tubules. ER stress is induced by a variety of stressors differing in their mechanism of action, including tunicamycin, thapsigargin, and the calcineurin inhibitor cyclosporine A. These ER stressors increased the UPR markers GRP78, GRP94, and phospho-eIF2α in human proximal tubular cells. Thapsigargin and cyclosporine A also increased cytosolic Ca2+ concentration and T cell death-associated gene 51 (TDAG51) expression, whereas tunicamycin did not. Thapsigargin was also shown to increase levels of active transforming growth factor (TGF)-β1 in the media of cultured human proximal tubular cells. Thapsigargin induced cytoskeletal rearrangement, β-catenin nuclear translocation, and α-smooth muscle actin and vinculin expression in proximal tubular cells, indicating an EMT response. Subconfluent primary human proximal tubular cells were induced to undergo EMT by TGF-β1 treatment. In contrast, tunicamycin treatment did not produce an EMT response. Plasmid-mediated overexpression of TDAG51 resulted in cell shape change and β-catenin nuclear translocation. These results allowed us to develop a two-hit model of ER stress-induced EMT, where Ca2+ dysregulation-mediated TDAG51 upregulation primes the cell for mesenchymal transformation via Wnt signaling and then TGF-β1 activation leads to a complete EMT response. Thus the release of Ca2+ from ER stores mediates EMT in human proximal tubular epithelium via the induction of TDAG51.
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Monteiro, Maria B., Susanne Ramm, Vidya Chandrasekaran, Sarah A. Boswell, Elijah J. Weber, Kevin A. Lidberg, Edward J. Kelly, and Vishal S. Vaidya. "A High-Throughput Screen Identifies DYRK1A Inhibitor ID-8 that Stimulates Human Kidney Tubular Epithelial Cell Proliferation." Journal of the American Society of Nephrology 29, no. 12 (October 25, 2018): 2820–33. http://dx.doi.org/10.1681/asn.2018040392.
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BackgroundThe death of epithelial cells in the proximal tubules is thought to be the primary cause of AKI, but epithelial cells that survive kidney injury have a remarkable ability to proliferate. Because proximal tubular epithelial cells play a predominant role in kidney regeneration after damage, a potential approach to treat AKI is to discover regenerative therapeutics capable of stimulating proliferation of these cells.MethodsWe conducted a high-throughput phenotypic screen using 1902 biologically active compounds to identify new molecules that promote proliferation of primary human proximal tubular epithelial cells in vitro.ResultsThe primary screen identified 129 compounds that stimulated tubular epithelial cell proliferation. A secondary screen against these compounds over a range of four doses confirmed that eight resulted in a significant increase in cell number and incorporation of the modified thymidine analog EdU (indicating actively proliferating cells), compared with control conditions. These eight compounds also stimulated tubular cell proliferation in vitro after damage induced by hypoxia, cadmium chloride, cyclosporin A, or polymyxin B. ID-8, an inhibitor of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), was the top candidate identified as having a robust proproliferative effect in two-dimensional culture models as well as a microphysiologic, three-dimensional cell culture system. Target engagement and genetic knockdown studies and RNA sequencing confirmed binding of ID-8 to DYRK1A and upregulation of cyclins and other cell cycle regulators, leading to epithelial cell proliferation.ConclusionsWe have identified a potential first-in-class compound that stimulates human kidney tubular epithelial cell proliferation after acute damage in vitro.
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Liukang, Chengyin, Jing Zhao, Jiaxin Tian, Min Huang, Rong Liang, Ye Zhao, and Guozhong Zhang. "Deciphering infected cell types, hub gene networks and cell-cell communication in infectious bronchitis virus via single-cell RNA sequencing." PLOS Pathogens 20, no. 5 (May 14, 2024): e1012232. http://dx.doi.org/10.1371/journal.ppat.1012232.
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Infectious bronchitis virus (IBV) is a coronavirus that infects chickens, which exhibits a broad tropism for epithelial cells, infecting the tracheal mucosal epithelium, intestinal mucosal epithelium, and renal tubular epithelial cells. Utilizing single-cell RNA sequencing (scRNA-seq), we systematically examined cells in renal, bursal, and tracheal tissues following IBV infection and identified tissue-specific molecular markers expressed in distinct cell types. We evaluated the expression of viral RNA in diverse cellular populations and subsequently ascertained that distal tubules and collecting ducts within the kidney, bursal mucosal epithelial cells, and follicle-associated epithelial cells exhibit susceptibility to IBV infection through immunofluorescence. Furthermore, our findings revealed an upregulation in the transcription of proinflammatory cytokines IL18 and IL1B in renal macrophages as well as increased expression of apoptosis-related gene STAT in distal tubules and collecting duct cells upon IBV infection leading to renal damage. Cell-to-cell communication unveiled potential interactions between diverse cell types, as well as upregulated signaling pathways and key sender-receiver cell populations after IBV infection. Integrating single-cell data from all tissues, we applied weighted gene co-expression network analysis (WGCNA) to identify gene modules that are specifically expressed in different cell populations. Based on the WGCNA results, we identified seven immune-related gene modules and determined the differential expression pattern of module genes, as well as the hub genes within these modules. Our comprehensive data provides valuable insights into the pathogenesis of IBV as well as avian antiviral immunology.
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Djudjaj, Sonja, Panagiotis Kavvadas, Niki Prakoura, Roman D. Bülow, Tiffany Migeon, Sandrine Placier, Christos E. Chadjichristos, Peter Boor, and Christos Chatziantoniou. "Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease." International Journal of Molecular Sciences 23, no. 2 (January 14, 2022): 884. http://dx.doi.org/10.3390/ijms23020884.
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Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions.
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Kazeminia, Sara, and Alfonso Eirin. "Role of mitochondria in endogenous renal repair." Clinical Science 138, no. 15 (July 30, 2024): 963–73. http://dx.doi.org/10.1042/cs20231331.
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Abstract Renal tubules have potential to regenerate and repair after mild-to-moderate injury. Proliferation of tubular epithelial cells represents the initial step of this reparative process. Although for many years, it was believed that proliferating cells originated from a pre-existing intra-tubular stem cell population, there is now consensus that surviving tubular epithelial cells acquire progenitor properties to regenerate the damaged kidney. Scattered tubular-like cells (STCs) are dedifferentiated adult renal tubular epithelial cells that arise upon injury and contribute to renal self-healing and recovery by replacing lost neighboring tubular epithelial cells. These cells are characterized by the co-expression of the stem cell surface markers CD133 and CD24, as well as mesenchymal and kidney injury markers. Previous studies have shown that exogenous delivery of STCs ameliorates renal injury and dysfunction in murine models of acute kidney injury, underscoring the regenerative potential of this endogenous repair system. Although STCs contain fewer mitochondria than their surrounding terminally differentiated tubular epithelial cells, these organelles modulate several important cellular functions, and their integrity and function are critical to preserve the reparative capacity of STCs. Recent data suggest that the microenviroment induced by cardiovascular risk factors, such as obesity, hypertension, and renal ischemia may compromise STC mitochondrial integrity and function, limiting the capacity of these cells to repair injured renal tubules. This review summarizes current knowledge of the contribution of STCs to kidney repair and discusses recent insight into the key role of mitochondria in modulating STC function and their vulnerability in the setting of cardiovascular disease.
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White, Lindsay R., Jason B. Blanchette, Li Ren, Ali Awn, Kiril Trpkov, and Daniel A. Muruve. "The characterization of α5-integrin expression on tubular epithelium during renal injury." American Journal of Physiology-Renal Physiology 292, no. 2 (February 2007): F567—F576. http://dx.doi.org/10.1152/ajprenal.00212.2006.
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The hallmark of progressive chronic kidney disease is the deposition of extracellular matrix proteins and tubulointerstitial fibrosis. Integrins mediate cell-extracellular matrix interaction and may play a role tubular epithelial injury. Murine primary tubular epithelial cells (TECs) express α5-integrin, a fibroblast marker and the natural receptor for fibronectin. Microscopy localized α5-integrin on E-cadherin-positive cells, confirming epithelial expression. The expression of α5-integrin increased in TECs grown on fibronectin and occurred in parallel with an upregulation of α-smooth muscle actin (αSMA), a marker of epithelial-mesenchymal transition (EMT). Exposure of TECs to transforming growth factor (TGF)-β also increased TEC α5-integrin expression in association with αSMA and EMT. Knock-down of α5-integrin expression with short interfering RNA attenuated the TGF-β induction of αSMA but did not alter morphologic EMT. Rather, α5-integrin was necessary for epithelial cell migration on fibronectin but not type IV collagen during cell spreading and epithelial wound healing in vitro. Immunohistochemistry revealed basolateral tubular epithelial α5-integrin expression in mouse kidneys after unilateral ureteric obstruction but not in contralateral control kidneys. In patient biopsies of nondiabetic kidney disease, α5-integrin expression was increased significantly in the renal interstitium. Focal basolateral staining was also detected in injured, but not in normal, tubular epithelium. In summary, these data show that TECs are induced to express α5-integrin during EMT and tubular epithelial injury in vitro and in vivo. These results increase our understanding of the biology of integrins during EMT and tubular injury in chronic kidney disease.
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Schwartz, John D., Francis Dumler, Jason M. Hafron, George D. Wilson, Stacy C. Wolforth, Michele T. Rooney, Wei Li, and Ping L. Zhang. "CD133 Staining Detects Acute Kidney Injury and Differentiates Clear Cell Papillary Renal Cell Carcinoma from Other Renal Tumors." ISRN Biomarkers 2013 (June 2, 2013): 1–8. http://dx.doi.org/10.1155/2013/353598.
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CD133 has recently been characterized as a progenitor cell marker in the kidney. However, the expression of this marker has not been thoroughly investigated in kidney injury and variants of renal tumors for pathology practice. We quantified CD133 expression in kidney biopsies from patients with acute renal failure and compared staining intensity with serum creatinine levels. CD133 expression levels were also evaluated in several subtypes of renal neoplasms. Normal adult renal parenchyma showed CD133 expression in parietal epithelium and in less than 5% of the epithelial cells in proximal and distal nephron tubules. However, CD133 was diffusely upregulated in the injured proximal and distal tubular epithelium and the CD133 expression scores in renal tubules were significantly correlated with serum creatinine levels. Amongst the renal tumors, CD133 was diffusely expressed in clear cell papillary renal cell carcinoma but was only focally present in other types of renal tumors. In summary, CD133 is a useful marker to detect renal tubular injury and to differentiate clear cell papillary renal cell carcinoma from other tumor types.
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Schiessl, Ina Maria, Alexandra Grill, Katharina Fremter, Dominik Steppan, Maj-Kristina Hellmuth, and Hayo Castrop. "Renal Interstitial Platelet-Derived Growth Factor Receptor-β Cells Support Proximal Tubular Regeneration." Journal of the American Society of Nephrology 29, no. 5 (February 23, 2018): 1383–96. http://dx.doi.org/10.1681/asn.2017101069.
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BackgroundThe kidney is considered to be a structurally stable organ with limited baseline cellular turnover. Nevertheless, single cells must be constantly replaced to conserve the functional integrity of the organ. PDGF chain B (PDGF-BB) signaling through fibroblast PDGF receptor-β (PDGFRβ) contributes to interstitial-epithelial cell communication and facilitates regenerative functions in several organs. However, the potential role of interstitial cells in renal tubular regeneration has not been examined.MethodsIn mice with fluorescent protein expression in renal tubular cells and PDGFRβ-positive interstitial cells, we ablated single tubular cells by high laser exposure. We then used serial intravital multiphoton microscopy with subsequent three-dimensional reconstruction and ex vivo histology to evaluate the cellular and molecular processes involved in tubular regeneration.ResultsSingle-tubular cell ablation caused the migration and division of dedifferentiated tubular epithelial cells that preceded tubular regeneration. Moreover, tubular cell ablation caused immediate calcium responses in adjacent PDGFRβ-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFRβ-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFRβ-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFRβ impeded PDGFRβ-positive cell migration to the tubular injury site and compromised the recovery of tubular function.Conclusions Ablated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFRβ-mediated communication between the renal interstitium and the tubular system.
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Akhtar, Muhammad Faheem, Ejaz Ahmad, Ilyas Ali, Muhammad Shafiq, and Zhe Chen. "The Effect of Inhibin Immunization in Seminiferous Epithelium of Yangzhou Goose Ganders: A Histological Study." Animals 11, no. 10 (September 26, 2021): 2801. http://dx.doi.org/10.3390/ani11102801.
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The current study investigated the effect of inhibin immunization on germ cell numbers (spermatogonia, spermatocytes, round, and elongated spermatids), seminiferous tubules (ST) diameter, Johnsen’s score, epithelial height (μm), luminal tubular diameter (μm), and number of ST per field (ST/field) of Yangzhou goose ganders. Histological evaluation showed apoptosis and regression of testes after inhibin (INH) immunization, with a concomitantly marked reduction in the round and elongated spermatids in the experiment (INH) group compared to the control group. The diameter of seminiferous tubules (ST) and epithelial height (EH) were positively correlated at 181, 200, and 227 days of age. In comparison, luminal tubular diameter (LD) was negatively correlated on day 227 to ST diameter and epithelial height. On day 227, many seminiferous tubules per field (ST/field) were negatively correlated to ST diameter, EH, and LD. INH immunization elevated ST diameter, EH, and LD, while Johnsen’s score and number of ST/field had reciprocal expression. In conclusion, the concomitant effect of INH immunization and seasonality in breeding regressed germ cells and damaged spermatogenesis in seminiferous epithelium Yangzhou ganders.
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Kanellis, John, Scott Fraser, Marina Katerelos, and David A. Power. "Vascular endothelial growth factor is a survival factor for renal tubular epithelial cells." American Journal of Physiology-Renal Physiology 278, no. 6 (June 1, 2000): F905—F915. http://dx.doi.org/10.1152/ajprenal.2000.278.6.f905.
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Vascular endothelial growth factor (VEGF) acts primarily as an endothelial cell mitogen via the “endothelial cell-specific” receptors VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR). Only a few nonendothelial cells have been shown to possess functional VEGF receptors. We therefore examined the rat renal tubular epithelial cell line NRK52-E. NRK52-E expressed VEGFR-1 and VEGFR-2 mRNA and protein by RT-PCR, Northern blotting, Western blotting, immunofluorescence, and ligand binding. Serum-starved NRK52-E incubated with VEGF showed a significant increase in [3H]thymidine incorporation compared with control (2.3-fold at 1–10 ng/ml, P < 0.05; 3.3-fold at 50–100 ng/ml, P < 0.01). VEGF also protected NRK52-E from hydrogen peroxide-induced apoptosis and necrosis compared with control (annexin-V-FITC-positive cells, 39 vs. 54%; viable cells, 50.5 vs. 39.7%). Immunohistochemical staining using a variety of antibodies showed expression of both VEGF receptors in normal rat renal tubules in vivo. Because VEGF induced a proliferative and an antiapoptotic response in renal tubular epithelial cells, these data suggest that VEGF may act as a survival factor for renal tubular epithelium in vivo.
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Kida, Yujiro, Kinji Asahina, Hirobumi Teraoka, Inna Gitelman, and Tetsuji Sato. "Twist Relates to Tubular Epithelial-Mesenchymal Transition and Interstitial Fibrogenesis in the Obstructed Kidney." Journal of Histochemistry & Cytochemistry 55, no. 7 (March 19, 2007): 661–73. http://dx.doi.org/10.1369/jhc.6a7157.2007.
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Epithelial-mesenchymal transition (EMT) is a critical step in renal fibrosis. It has been recently reported that a transcription factor, Twist, plays a pivotal role in metastasis of breast tumors by inducing EMT. In this study, we examined whether Twist relates to renal fibrogenesis including EMT of tubular epithelia, evaluating Twist expression level in the unilateral ureteral obstruction (UUO) model. Kidneys of mice subjected to UUO were harvested 1, 3, 7, and 10 days after obstruction. Compared with control kidneys, Twist mRNA-level significantly increased 3 days after UUO (UUO day 3 kidney) and further augmented until 10 days after UUO. Twist expression increased in tubular epithelia of the dilated tubules and the expanded interstitial areas of UUO kidneys, where cell-proliferating appearances were frequently found in a time-dependent manner. Although a part of tubular cells in whole nephron segment were immunopositive for Twist in UUO day 7 kidneys, tubular epithelia downstream of nephron more frequently expressed Twist than upstream of nephron. In UUO day 7 kidneys, some tubular epithelia were confirmed to coexpress Twist and fibroblast-specific protein-1, a marker for EMT, indicating that Twist is involved in tubular EMT under pathological state. Twist was expressed also in a number of α-smooth muscle actin-positive myofibroblasts located in the expanded interstitial area of UUO kidneys. From these findings, the present investigation suggests that Twist is associated with tubular EMT, proliferation of myofibroblasts, and subsequent renal fibrosis in obstructed kidneys.
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Koide, Naoki, Kayo Narita, Yutaka Kato, Tsuyoshi Sugiyama, Dipshikha Chakravortty, Akiko Morikawa, Tomoaki Yoshida, and Takashi Yokochi. "Expression of Fas and Fas Ligand on Mouse Renal Tubular Epithelial Cells in the Generalized Shwartzman Reaction and Its Relationship to Apoptosis." Infection and Immunity 67, no. 8 (August 1, 1999): 4112–18. http://dx.doi.org/10.1128/iai.67.8.4112-4118.1999.
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ABSTRACT Previously we reported that the consecutive injection of lipopolysaccharide (LPS) into LPS-sensitized mice for the generalized Shwartzman reaction (GSR) appeared to induce the injury of renal tubular epithelial cells via apoptosis. The aim of this study was to characterize the mechanism of renal tubular epithelial cell injury in GSR. The expression of Fas and Fas ligand was immunohistochemically detected on renal tubular epithelial cells from GSR-induced mice, although neither Fas nor Fas ligand was found in cells from untreated control mice or in cells from mice receiving a single injection of LPS. GSR-induced renal tubular epithelial cell injury was produced in neither Fas-negative MRL-lpr/lpr mice nor Fas ligand-negative MRL-gld/gld mice. The administration of anti-gamma interferon antibody together with a preparative injection of LPS prevented the expression of Fas and Fas ligand and the apoptosis of renal tubular epithelial cells. A provocative injection of tumor necrosis factor alpha into LPS-sensitized mice augmented Fas and Fas ligand expression and the apoptosis of renal tubular epithelial cells. The administration of tumor necrosis factor alpha to interleukin-12-sensitized mice resulted in Fas and Fas ligand expression and the apoptosis. Sensitization with interleukin-12 together with anti-gamma interferon antibody did not cause the apoptosis of renal tubular epithelial cells. It was suggested that the Fas/Fas ligand system probably plays a critical role in the development of renal tubular epithelial cell injury through apoptotic cell death.
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Aydin, Sonia, Sara Signorelli, Thomas Lechleitner, Michael Joannidis, Clara Pleban, Paul Perco, Walter Pfaller, and Paul Jennings. "Influence of microvascular endothelial cells on transcriptional regulation of proximal tubular epithelial cells." American Journal of Physiology-Cell Physiology 294, no. 2 (February 2008): C543—C554. http://dx.doi.org/10.1152/ajpcell.00307.2007.
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In the renal cortex the peritubular capillary network and the proximal tubular epithelium cooperate in solute and water reabsorption, secretion, and inflammation. However, the mechanisms by which these two cell types coordinate such diverse functions remain to be characterized. Here we investigated the influence of microvascular endothelial cells on proximal tubule cells, using a filter-based, noncontact, close-proximity coculture of the human microvascular endothelial cell line HMEC-1 and the human proximal tubular epithelial cell line HK-2. With the use of DNA microarrays the transcriptomes of HK-2 cells cultured in mono- and coculture were compared. HK-2 cells in coculture exhibited a differential expression of 99 genes involved in pathways such as extracellular matrix (e.g., lysyl oxidase), cell-cell communication (e.g., IL-6 and IL-1β), and transport (e.g., GLUT3 and lipocalin 2). HK-2 cells also exhibited an enhanced paracellular gating function in coculture, which was dependent on HMEC-1-derived extracellular matrix. We identified a number of HMEC-1-enriched genes that are potential regulators of epithelial cell function such as extracellular matrix proteins (e.g., collagen I, III, IV, and V, laminin-α IV) and cytokines/growth factors (e.g., hepatocyte growth factor, endothelin-1, VEGF-C). This study demonstrates a complex network of communication between microvascular endothelial cells and proximal tubular epithelial cells that ultimately affects proximal tubular cell function. This coculture model and the data described will be important in the further elucidation of microvascular endothelial and proximal tubular epithelial cross talk mechanisms.
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LORZ, CORINA, ALBERTO ORTIZ, PILAR JUSTO, SILVIA GONZÁLEZ-CUADRADO, NATALIA DUQUE, CARMEN GÓMEZ-GUERRERO, and JESÚS EGIDO. "Proapoptotic Fas Ligand Is Expressed by Normal Kidney Tubular Epithelium and Injured Glomeruli." Journal of the American Society of Nephrology 11, no. 7 (July 2000): 1266–77. http://dx.doi.org/10.1681/asn.v1171266.
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Abstract. Fas ligand (FasL) is a cell membrane cytokine that can promote apoptosis through activation of Fas receptors. Fas receptor activation induces glomerular cell apoptosisin vivoand participates in tubular cell death during acute renal failure. However, there is little information on the expression of FasL in the kidney. This study reports that FasL mRNA and protein are present in normal mouse and rat kidney.In situhybridization and immunohistochemistry showed that proximal tubular epithelium is the main site of FasL expression in the normal kidney. In addition, increased total kidney FasL mRNA andde novoFasL protein expression by glomerular cells were observed in two different models of glomerular injury : rat immune-complex proliferative glumerulonephritis and murine lupus nephritis. Both full-length and soluble FasL were increased in the kidneys of the mice with nephritis. Cultured murine proximal tubular epithelial MCT cells and primary cultures of murine tubular epithelial cells expressed FasL mRNA and protein. Tubular epithelium-derived FasL induced apoptosis in Fassensitive lymphoid cell lines but not in Fas-resistant lymphoid cell lines. By contrast, MCT cells grown in the presence of the survival factors of serum were resistant to FasL, and only became partially sensitive to apoptosis induced by high concentrations (100 ng/ml) of FasL upon serum deprivation. However, MCT cells stimulated with inflammatory mediators (tumor necrosis factor-α, interferon-γ, and lipopolysaccharide) increased cell surface Fas expression and were sensitized to apoptosis induced by FasL (FasL 55 ± 5%versuscontrol 8.3 ± 4.1% apoptotic cells at 24 h,P< 0.05). Cytokine-primed primary cultures of tubular epithelial cells also acquired sensitivity to FasL-induced apoptosis. These results suggest that FasL expression by intrinsic renal cells may play a role in cell homeostasis in the normal kidney and during renal injury.
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Mao, Haiping, Zhilian Li, Yi Zhou, Zhijian Li, Shougang Zhuang, Xin An, Baiyu Zhang, et al. "HSP72 attenuates renal tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy." American Journal of Physiology-Renal Physiology 295, no. 1 (July 2008): F202—F214. http://dx.doi.org/10.1152/ajprenal.00468.2007.
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Although heat shock protein 72 kDa (HSP72) protects tubular epithelium from a variety of acute insults, its role in chronic renal injury and fibrosis is poorly characterized. In this study, we tested the hypothesis that HSP72 reduces apoptosis and epithelial-to-mesenchymal transition (EMT), important contributors to tubular cell injury in vitro and in vivo. In rats, orally administered geranylgeranylacetone (GGA), an agent that selectively induces HSP72, markedly reduced both apoptosis and cell proliferation in tubular epithelium and decreased both interstitial fibroblast accumulation and collagen I deposition after unilateral ureteric obstruction, a model of chronic renal tubulointerstitial fibrosis and dysfunction. In cultured renal NRK52E cells, exposure to TGF-β1 induced EMT and apoptosis, major causes of renal fibrosis and tubular atrophy, respectively. Exposure to a pan-caspase inhibitor (ZVAD-FMK) prevented TGF-β1-induced apoptosis but did not reduce EMT. In contrast, selective HSP72 expression in vitro inhibited EMT caused by TGF-β1 as indicated by preserving the E-cadherin expression level and α-smooth muscle actin induction. Small interfering RNA directed against HSP72 blocked the cytoprotective effects of HSP72 overexpression on EMT in TGF-β1-exposed cells. Taken together, our data indicate that HSP72 ameliorates renal tubulointerstitial fibrosis in obstructive nephropathy by inhibiting both renal tubular epithelial cell apoptosis and EMT.
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Nishihara, Kumiko, Satohiro Masuda, Shunsaku Nakagawa, Atsushi Yonezawa, Takaharu Ichimura, Joseph V. Bonventre, and Ken-ichi Inui. "Impact of Cyclin B2 and Cell division cycle 2 on tubular hyperplasia in progressive chronic renal failure rats." American Journal of Physiology-Renal Physiology 298, no. 4 (April 2010): F923—F934. http://dx.doi.org/10.1152/ajprenal.00567.2009.
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To clarify the specific molecular events of progressive tubular damage in chronic renal failure (CRF), we conducted microarray analyses using isolated proximal tubules from subtotally nephrectomized (Nx) rats as a model of CRF. Our results clearly demonstrated time-dependent changes in gene expression profiles localized to proximal tubules. The expression of mitosis-specific genes Cyclin B2 and Cell division cycle 2 (Cdc2) was significantly and selectively increased in the proximal tubules during the compensated period but decreased to basal level in the end-stage period. Administration of everolimus, a potent inhibitor of mammalian target of rapamycin, markedly reduced compensatory hypertrophy and hyperplasia of epithelial cells, which was accompanied by complete abolishment of the expression of Cyclin B2 and Cdc2 enhancement; renal function was then severely decreased. Treatment with the Cdc2 inhibitor 2-cyanoethyl alsterpaullone clearly decreased epithelial cell hyperplasia, based on staining of phosphorylated histone H3 and Ki-67, while hypertrophy was not inhibited. In conclusion, we have demonstrated roles of Cyclin B2 and Cdc2 in the epithelial hyperplasia in response to Nx. These results advance the knowledge of the contribution of cell cycle regulators, especially M phase, in pathophysiology of tubular restoration and/or degeneration, and these two molecules are suggested to be a marker for the proliferation of proximal tubular cells in CRF.
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Ng, Yan-Fei, Chang-Yin Choinh, Marvin Raden Torres De Guzman, Chandramouli Nagarajan, and Hwai-Liang Loh. "Lambda light chain crystalline proximal tubulopathy with probable light chain cast nephropathy and clonal plasma cell infiltrate – uncommon manifestations of a rare form of multiple myeloma." Journal of Nephropathology 10, no. 1 (May 13, 2020): e08-e08. http://dx.doi.org/10.34172/jnp.2021.08.
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Light chain proximal tubulopathy (LCPT) is an uncommon renal disease characterized by the accumulation of monoclonal light chains within proximal tubular epithelial cells, with or without crystal formation. We report a rare case of lambda LCPT with crystals. Renal biopsy showed substantial acute tubular injury with unusual cytoplasmic changes affecting proximal tubules. In addition, abnormal tubular casts suggested concomitant light chain cast nephropathy. A clonal plasma cell infiltrate was present in the tubulointerstitial compartment. Immunofluorescence demonstrated strong staining for lambda light chain in tubular epithelial cells. Despite the absence of discernible crystals on light microscopy (LM), they were readily identified when ultrastructural evaluation was undertaken. Crystalline inclusions demonstrated positive immunogold labelling for lambda.
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Xu, Dan, Panpan Chen, Bao Wang, Yanzhe Wang, Naijun Miao, Fan Yin, Qian Cheng, et al. "NIX-mediated mitophagy protects against proteinuria-induced tubular cell apoptosis and renal injury." American Journal of Physiology-Renal Physiology 316, no. 2 (February 1, 2019): F382—F395. http://dx.doi.org/10.1152/ajprenal.00360.2018.
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Proteinuria, the most common symptom of renal injury, is an independent factor for renal tubular injury. However, the underlying mechanism remains to be fully elucidated. Mitochondrion is an important target for proteinuria-induced renal tubular cell injury. Insufficient mitophagy exacerbates cell injury by initiating mitochondrial dysfunction-related cell apoptosis. In the experiment, the role of NIP3-like protein X (NIX)-mediated mitophagy was investigated in proteinuria-induced renal injury. In this study, we demonstrated that NIX expression was reduced in renal tubules and correlated with the decline of estimated glomerular filtration rate and increase of the proteinuria in patients. In proteinuric mice, NIX-mediated mitophagy was significantly suppressed. Meanwhile, the proteinuric mice exhibited renal dysfunction, increased mitochondrial fragmentation, and tubular cell apoptosis. Overexpression of NIX attenuated those disruptions in proteinuric mice. In cultured renal tubular epithelial cells, albumin induced a decrease in NIX-mediated mitophagy and an increase in cell apoptosis. Overexpression of NIX attenuated albumin-induced cell apoptosis, whereas NIX siRNA aggravated these perturbations. These results indicate that proteinuria suppresses NIX-mediated mitophagy in the renal tubular epithelial cell, which triggers the cell undergoing mitochondria-dependent cell apoptosis. Collectively, our finding suggests that restoration of NIX-mediated mitophagy might be a novel therapeutic target for alleviating proteinuria-induced kidney injury.
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Zuk, Anna, Joseph V. Bonventre, Dennis Brown, and Karl S. Matlin. "Polarity, integrin, and extracellular matrix dynamics in the postischemic rat kidney." American Journal of Physiology-Cell Physiology 275, no. 3 (September 1, 1998): C711—C731. http://dx.doi.org/10.1152/ajpcell.1998.275.3.c711.
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Acute renal failure (ARF) as a consequence of ischemic injury is a common disease affecting 5% of the hospitalized population. Despite the fact that mortality from ARF is high, there has been little improvement in survival rates over the last 40 years. The pathogenesis of ARF may be related to substantial changes in cell-cell and cell-extracellular matrix interactions mediated by β1-integrins. On the basis of in vitro and in vivo studies, reorganization of β1-integrins from basal to apical surfaces of injured tubular epithelia has been suggested to facilitate epithelial detachment, contributing to tubular obstruction and backleak of glomerular filtrate. In this study, we examine integrin and extracellular matrix dynamics during epithelial injury and repair using an in vivo rat model of unilateral ischemia. We find that, soon after reperfusion, β1-integrins newly appear on lateral borders in epithelial cells of the S3 segment but are not on the apical surface. At later times, as further injury and regeneration coordinately occur, epithelia adherent to the basement membrane localize β1 predominantly to basal surfaces even while the polarity of other marker proteins is lost. At the same time, amorphous material consisting of depolarized exfoliated cells fills the luminal space. Notably, β1-integrins are not detected on exfoliated cells. A novel finding is the presence of fibronectin, a glycoprotein of plasma and the renal interstitium, in tubular spaces of the distal nephron and to a lesser extent S3 segments. These results indicate that β1-integrins dramatically change their distribution during ischemic injury and epithelial repair, possibly contributing to cell exfoliation initially and to epithelial regeneration at later stages. Together with the appearance of large amounts of fibronectin in tubular lumens, these alterations may play a significant role in the pathophysiology of ARF.
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Sarró, Eduard, Mónica Durán, Ana Rico, Diana Bou-Teen, Vanesa Fernández-Majada, Anthony J. Croatt, Karl A. Nath, et al. "Cyclophilins A and B oppositely regulate renal tubular epithelial cell phenotype." Journal of Molecular Cell Biology 12, no. 7 (March 12, 2020): 499–514. http://dx.doi.org/10.1093/jmcb/mjaa005.
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Abstract Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial–mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGFβ)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFβ-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.
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Trabelsi, Amel, Wided Stita, Mohamed Tahar Yacoubi, Soumaya Rammeh, Sihem Hmissa, and Sadok Korbi. "Renal mucinous tubular and spindle cell carcinoma." Canadian Urological Association Journal 2, no. 6 (December 1, 2008): 635. http://dx.doi.org/10.5489/cuaj.984.
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We report a case of mucinous tubular and spindle cell carcinoma in a 66-year old woman. The tumour, located on the left kidney, was well circumscribed. Microscopically, the tumour was composed of cuboidal cells arranged in tubules and making abrupt transitions to spindle cell morphology in a myxoid stroma. Tumour cells were strongly positive for cytokeratin 7 and epithelial membrane antigen. Because of the favourable prognosis with this type of tumour, mucinous tubular and spindle cell carcinoma must be differentiated from papillary renal cell carcinoma, especially that with sarcomatoid change. No tumour recurrence or metastasis were reported with a follow-up of 23 months.
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Zhang, Wei, Lingling Xing, Lu Xu, Xiaoxue Jin, Yunxia Du, Xiaojuan Feng, Shuxia Liu, and Qingjuan Liu. "Nudel involvement in the high-glucose-induced epithelial-mesenchymal transition of tubular epithelial cells." American Journal of Physiology-Renal Physiology 316, no. 1 (January 1, 2019): F186—F194. http://dx.doi.org/10.1152/ajprenal.00218.2018.
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Nudel is a newly discovered factor related to cell migration. The tubular epithelial-mesenchymal transition (EMT) includes four steps: the loss of the adhesive properties of epithelial cells, the acquisition of a mesenchymal cell phenotype, the destruction of the tubular basal membrane, and the migration into the renal interstitium. The purpose of this study was to investigate the role of Nudel in the high-glucose-induced EMT of tubular epithelial cells. Human renal proximal tubular epithelial cells (HKCs) were treated with Nudel shRNA to clarify the role and mechanism of Nudel in tubular EMT induced by high glucose. We found that Nudel was expressed at a high level in high-glucose-stimulated HKCs, and the expression of Nudel was associated with the activation of signal transducer and activator of transcription 3. After transfection with Nudel shRNA, we detected the expression levels of E-cadherin, α-smooth muscle actin (α-SMA), and the Wiskott-Aldrich syndrome family of proteins (including WASP, N-WASP, WAVE1, WAVE2, and WAVE3) via assay. Cell migration was analyzed by the scratching method. The results showed that high glucose downregulated E-cadherin expression, upregulated α-SMA expression, and promoted the migration of HKCs. The expression levels of N-WASP, WAVE1, and WAVE2 were also elevated in HKCs treated with high glucose. All changes induced by high glucose were ameliorated by Nudel depletion. We conclude that Nudel participates in the transition and the migration of tubular epithelial cells via the regulation of WASP family proteins.
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Frangié, Carlos, Wenhui Zhang, Joëlle Perez, Yi-Chun Xu Dubois, Jean-Philippe Haymann, and Laurent Baud. "Extracellular Calpains Increase Tubular Epithelial Cell Mobility." Journal of Biological Chemistry 281, no. 36 (July 5, 2006): 26624–32. http://dx.doi.org/10.1074/jbc.m603007200.
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Couchman, John R., Yashi Mahalingam, and Anna C. Erickson. "Basement membrane and tubular epithelial cell behaviour." International Journal of Experimental Pathology 85, no. 1 (June 28, 2008): A6—A7. http://dx.doi.org/10.1111/j.0959-9673.2004.0369d.x.
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Li, Ling, Diana Zepeda-Orozco, Vishal Patel, Phu Truong, Courtney M. Karner, Thomas J. Carroll, and Fangming Lin. "Aberrant planar cell polarity induced by urinary tract obstruction." American Journal of Physiology-Renal Physiology 297, no. 6 (December 2009): F1526—F1533. http://dx.doi.org/10.1152/ajprenal.00318.2009.
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Flow sensing by primary cilia of the epithelial cells is involved in cystogenesis in polycystic kidney disease. We investigate whether a similar mechanism applies to the pathogenesis of cyst-like tubular dilatation induced by ureteral obstruction in mice. Robust proliferation occurs in the obstructed tubules when urine flow is interrupted as well as in the repairing tubules when urine flow is reestablished after relief of the obstruction, suggesting a urine flow-independent mechanism of proliferation. In the urothelium, proliferation is only detected above the obstruction, although urine flow ceased both above and below the obstruction. Our results support mechanical strain- rather than flow-mediated proliferation in obstructive uropathy. To understand the mechanism of cell proliferation leading to increased tubular diameter in cyst-like tubular dilatation, we examine planar cell polarity (PCP), which is necessary for oriented cell division and maintenance of tubular diameter. In dilated tubules, the orientation of cell division is randomized, atypical PKC (aPKC) is mislocalized, and the pattern of the expression of a core PCP protein, Frizzled3 (Fz3), is altered. In addition, the level of Fz3 expression is increased. These results indicate that aberrant PCP may contribute to cyst-like tubular dilatation in obstructive uropathy. Interestingly, the orientation of cell division, localization of aPKC, and Fz3 expression return to normal when obstruction is relieved, which suggest a role of normal PCP signaling in tubular repair.
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Schelling, Jeffrey R., and Bassam G. Abu Jawdeh. "Regulation of cell survival by Na+/H+exchanger-1." American Journal of Physiology-Renal Physiology 295, no. 3 (September 2008): F625—F632. http://dx.doi.org/10.1152/ajprenal.90212.2008.
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Na+/H+exchanger-1 (NHE1) is a ubiquitous plasma membrane Na+/H+exchanger typically associated with maintenance of intracellular volume and pH. In addition to the NHE1 role in electroneutral Na+/H+transport, in renal tubular epithelial cells in vitro the polybasic, juxtamembrane NHE1 cytosolic tail domain acts as a scaffold, by binding with ezrin/radixin/moesin (ERM) proteins and phosphatidylinositol 4,5-bisphosphate, which initiates formation of a signaling complex that culminates in Akt activation and opposition to initial apoptotic stress. With robust apoptotic stimuli renal tubular epithelial cell NHE1 is a caspase substrate, and proteolytic cleavage may permit progression to apoptotic cell death. In vivo, genetic or pharmacological NHE1 loss of function causes renal tubule epithelial cell apoptosis and renal dysfunction following streptozotocin-induced diabetes, ureteral obstruction, and adriamycin-induced podocyte toxicity. Taken together, substantial in vivo and in vitro data demonstrate that NHE1 regulates tubular epithelial cell survival. In contrast to connotations of NHE1 as an unimportant “housekeeping” protein, this review highlights that NHE1 activity is critical for countering tubular atrophy and chronic renal disease progression.
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Miya, Masaaki, Akito Maeshima, Keiichiro Mishima, Noriyuki Sakurai, Hidekazu Ikeuchi, Takashi Kuroiwa, Keiju Hiromura, Hideaki Yokoo, and Yoshihisa Nojima. "Enhancement of in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury." American Journal of Physiology-Renal Physiology 301, no. 2 (August 2011): F387—F395. http://dx.doi.org/10.1152/ajprenal.00619.2010.
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Renal proximal tubular epithelium can regenerate after various insults. To examine whether the tubular repair process is regulated by surrounding peritubular capillaries, we established an in vitro human tubulogenesis model that mimics in vivo tubular regeneration after injury. In this model, HGF, a potent renotropic factor, dose dependently induced tubular structures in human renal proximal tubular epithelial cells cultured in gels. Consistent with regenerating tubular cells after injury, HGF-induced tubular structures expressed a developmental gene, Pax-2, and a mesenchymal marker, vimentin, and formed a lumen with aquaporin-1 expression. Electron microscopic analysis showed the presence of microvilli on the apical site of the lumen, suggesting that these structures are morphologically equivalent to renal tubules in vivo. When cocultured with human umbilical vein endothelial cells (HUVEC), HGF-induced tubular formation was significantly enhanced. This could not be reproduced by the addition of VEGF, basic FGF, or PDGF. Protein array revealed that HUVEC produced various matrix metalloproteinases (MMPs). The stimulatory effects of coculture with HUVEC or HUVEC-derived conditional medium were almost completely abolished by addition of the tissue inhibitor of metalloproteinase (TIMP)-1 or TIMP-2. These data suggest that endothelial cell-derived factors including MMPs play a critical role in tubulogenesis and imply a potential role of peritubular capillary endothelium as a source of factor(s) required for tubular recovery after injury.
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Yan, Qunsheng, Yang Chen, Haoran Liu, Guoxiang Li, Chaozhao Liang, and Zongyao Hao. "Effects of alternative splicing events and transcriptome changes on kidney stone formation." Urolithiasis 50, no. 2 (January 8, 2022): 131–40. http://dx.doi.org/10.1007/s00240-021-01293-z.
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AbstractDuring the development of urinary stone disease, the formation of tiny crystals that adhere to the renal tubular epithelium induces epithelial cell damage. This damage and repair of the epithelium is associated with the establishment of more crystal adhesion sites, which in turn stimulates further crystal adhesion and, eventually, stone formation. Deposited crystals typically cause changes in epithelial cell gene expression, such as transcriptome changes and alternative splicing events. Although considered important for regulating gene expression, alternative splicing has not been reported in studies related to kidney stones. To date, whether alternative splicing events are involved in the regulation of stone formation and whether crystallographic cell interactions are regulated by alternative splicing at the transcriptional level have remained unknown. Therefore, we conducted RNA sequencing and alternative splicing-related bioassays by modeling the in vitro stone environment. Many alternative splicing events were associated with crystallographic cell interactions. Moreover, these events regulated transcription and significantly affected the capacity of crystals to adhere to renal tubular epithelial cells and regulate apoptosis.
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Hills, Claire, Gareth William Price, Mark John Wall, Timothy John Kaufmann, Chi-Wai Tang, Wai Han Yiu, and Paul Edward Squires. "Transforming Growth Factor Beta 1 Drives a Switch in Connexin Mediated Cell-to-Cell Communication in Tubular Cells of the Diabetic Kidney." Cellular Physiology and Biochemistry 45, no. 6 (2018): 2369–88. http://dx.doi.org/10.1159/000488185.
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Background/Aims: Changes in cell-to-cell communication have been linked to several secondary complications of diabetes, but the mechanism by which connexins affect disease progression in the kidney is poorly understood. This study examines a role for glucose-evoked changes in the beta1 isoform of transforming growth factor (TGFβ1), on connexin expression, gap-junction mediated intercellular communication (GJIC) and hemi-channel ATP release from tubular epithelial cells of the proximal renal nephron. Methods: Biopsy material from patients with and without diabetic nephropathy was stained for connexin-26 (CX26) and connexin-43 (CX43). Changes in expression were corroborated by immunoblot analysis in human primary proximal tubule epithelial cells (hPTECs) and model epithelial cells from human renal proximal tubules (HK2) cultured in either low glucose (5mmol/L) ± TGFβ1 (2-10ng/ml) or high glucose (25mmol/L) for 48h or 7days. Secretion of the cytokine was determined by ELISA. Paired whole cell patch clamp recordings were used to measure junctional conductance in control versus TGFβ1 treated (10ng/ml) HK2 cells, with carboxyfluorescein uptake and ATP-biosensing assessing hemi-channel function. A downstream role for ATP in mediating the effects of TGF-β1 on connexin mediated cell communication was assessed by incubating cells with ATPγS (1-100µM) or TGF-β1 +/- apyrase (5 Units/ml). Implications of ATP release were measured through immunoblot analysis of interleukin 6 (IL-6) and fibronectin expression. Results: Biopsy material from patients with diabetic nephropathy exhibited increased tubular expression of CX26 and CX43 (P<0.01, n=10), data corroborated in HK2 and hPTEC cells cultured in TGFβ1 (10ng/ml) for 7days (P<0.001, n=3). High glucose significantly increased TGFβ1 secretion from tubular epithelial cells (P<0.001, n=3). The cytokine (10ng/ml) reduced junctional conductance between HK2 cells from 4.5±1.3nS in control to 1.15±0.9nS following 48h TGFβ1 and to 0.42±0.2nS after 7days TGFβ1 incubation (P<0.05, n=5). Acute (48h) and chronic (7day) challenge with TGFβ1 produced a carbenoxolone (200µM)-sensitive increase in carboxyfluorescein loading, matched by an increase in ATP release from 0.29±0.06μM in control to 1.99±0.47μM after 48hr incubation with TGFβ1 (10ng/ml; P<0.05, n=3). TGF-β1 (2-10ng/ml) and ATPγs (1-100µM) increased expression of IL-6 (P<0.001 n=3) and fibronectin (P<0.01 n=3). The effect of TGF-β1 on IL-6 and fibronectin expression was partially blunted when preincubated with apyrase (n=3). Conclusion: These data suggest that chronic exposure to glucose-evoked TGFβ1 induce an increase in CX26 and CX43 expression, consistent with changes observed in tubular epithelia from patients with diabetic nephropathy. Despite increased connexin expression, direct GJIC communication decreases, whilst hemichannel expression/function and paracrine release of ATP increases, changes that trigger increased levels of expression of interleukin 6 and fibronectin. Linked to inflammation and fibrosis, local increases in purinergic signals may exacerbate disease progression and highlight connexin mediated cell communication as a future therapeutic target for diabetic nephropathy.
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TUFRO, ALDA, VICTORIA F. NORWOOD, ROBERT M. CAREY, and R. ARIEL GOMEZ. "Vascular Endothelial Growth Factor Induces Nephrogenesis and Vasculogenesis." Journal of the American Society of Nephrology 10, no. 10 (October 1999): 2125–34. http://dx.doi.org/10.1681/asn.v10102125.
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Abstract. The expression of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and Flk-1 in the rat kidney was examined during ontogeny using Northern blot analysis and immunocytochemistry. In prevascular embryonic kidneys (embryonic day 14 [E14]), immunoreactive Flt-1 and Flk-1 were observed in isolated angioblasts, whereas VEGF was not detected. Angioblasts aligned forming cords before morphologically differentiating into endothelial cells. In late fetal kidneys (E19), immunoreactive VEGF was detected in glomerular epithelial and tubular cells, whereas Flt-1 and Flk-1 were expressed in contiguous endothelial cells. To determine whether VEGF induces endothelial cell differentiation and vascular development in the kidney, the effect of recombinant human VEGF (5 ng/ml) was examined on rat metanephric organ culture, a model known to recapitulate nephrogenesis in the absence of vessels. After 6 d in culture in serum-free, defined media, metanephric kidney growth and morphology were assessed. DNA content was higher in VEGF-treated explants (1.9 ± 0.17 μg/kidney, n = 9) than in paired control explants (1.4 ± 0.10 μg/kidney, n = 9) (P < 0.05). VEGF induced proliferation of tubular epithelial cells, as indicated by an increased number of tubules and tubular proliferating cell nuclear antigen-containing cells. VEGF induced upregulation of Flk-1 and Flt-1 expression, as assessed by Western blot analysis. Developing endothelial cells were identified and localized using immunocytochemistry and electron microscopy. Flt-1, Flk-1, and angiotensin-converting enzyme-containing cells were detected in VEGF-treated explants, whereas control explants were negative. These studies confirmed previous reports indicating that the expression of VEGF and its receptors is temporally and spatially associated with kidney vascularization and identified angioblasts expressing Flt-1 and Flk-1 in prevascular embryonic kidneys. The data indicate that VEGF expression is downregulated in standard culture conditions and that VEGF stimulates growth of embryonic kidney explants by expanding both endothelium and epithelium, resulting in vasculogenesis and enhanced tubulogenesis. These data suggest that VEGF plays a critical role in renal development by promoting endothelial cell differentiation, capillary formation, and proliferation of tubular epithelia.
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Iida, Manami, Shuichi Ohtomo, Naoko A. Wada, Otoya Ueda, Yoshinori Tsuboi, Atsuo Kurata, Kou-ichi Jishage, and Naoshi Horiba. "TNF-α induces Claudin-1 expression in renal tubules in Alport mice." PLOS ONE 17, no. 3 (March 10, 2022): e0265081. http://dx.doi.org/10.1371/journal.pone.0265081.
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Claudin-1 (CL-1) is responsible for the paracellular barrier function of glomerular parietal epithelial cells (PEC) in kidneys, but the role of CL-1 in proximal tubules remains to be elucidated. In this study, to evaluate CL-1 as a potential therapeutic drug target for chronic kidney disease, we investigated change of CL-1 expression in the proximal tubules of diseased kidney and elucidated the factors that induced this change. We established Alport mice as a kidney disease model and investigated the expression of CL-1 in diseased kidney using quantitative PCR and immunohistochemistry (IHC). Compared to wild type mice, Alport mice showed significant increases in plasma creatinine, urea nitrogen and urinary albumin excretion. CL-1 mRNA was increased significantly in the kidney cortex and CL-1 was localized on the adjacent cell surfaces of PECs and proximal tubular epithelial cells. The infiltration of inflammatory cells around proximal tubules and a significant increase in TNF-α mRNA were observed in diseased kidneys. To reveal factors that induce CL-1, we analyzed the induction of CL-1 by albumin or tumor necrosis factor (TNF)-α in human proximal tubular cells (RPTEC/TERT1) using quantitative PCR and Western blotting. TNF-α increased CL-1 expression dose-dependently, though albumin did not affect CL-1 expression in RPTEC/TERT1. In addition, both CL-1 and TNF-α expression were significantly increased in UUO mice, which are commonly used as a model of tubulointerstitial inflammation without albuminuria. These results indicate that CL-1 expression is induced by inflammation, not by albuminuria in diseased proximal tubules. Moreover, we examined the localization of CL-1 in the kidney of IgA nephropathy patients by IHC and found CL-1 expression was also elevated in the proximal tubular cells. Taken together, CL-1 expression is increased in the proximal tubular epithelial cells of diseased kidney. Inflammatory cells around the tubular epithelium may produce TNF-α which in turn induces CL-1 expression.
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Kim, Jinu, Kyong-Jin Jung, and Kwon Moo Park. "Reactive oxygen species differently regulate renal tubular epithelial and interstitial cell proliferation after ischemia and reperfusion injury." American Journal of Physiology-Renal Physiology 298, no. 5 (May 2010): F1118—F1129. http://dx.doi.org/10.1152/ajprenal.00701.2009.
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Reactive oxygen species (ROS) function as an inducer of cell death and survival or proliferative factor, in a cell-type-specific and concentration-dependent manner. All of these roles are critical to ischemia-induced renal functional impairment and progressive fibrotic changes in the kidney. In an effort to define the role of ROS in the proliferation of tubular epithelial cells and of interstitial cells in kidneys recovering after ischemia and reperfusion (I/R) injury, experimental mice were subjected to 30 min of bilateral kidney ischemia and administered with manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP), a superoxide dismutase mimetic, from 2 to 15 days after I/R for 14 days daily (earlier and longer) and from 8 to 15 days after I/R for 8 days daily (later and shorter). Cell proliferation was assessed via 5′-bromo-2′-deoxyuridine (BrdU) incorporation assays for 20 h before the harvest of kidneys. After I/R, the numbers of BrdU-incorporating cells increased both in the tubules and interstitium. MnTMPyP administration was shown to accelerate the proliferation of tubular epithelial cells, presenting tubule-specific marker proteins along tubular segments, whereas it attenuated the proliferation of interstitial cells, evidencing α-smooth muscle actin, fibroblast-specific protein-1, F4/80, and NADPH oxidase-2 proteins; these results indicated that ROS attenuates tubular cell regeneration, but accelerates interstitial cell proliferation. Earlier and longer MnTMPyP treatment more effectively inhibited tissue superoxide formation, the increment of interstitial cells, and the decrement of epithelial cells compared with later and shorter treatment. After I/R, apoptotic cells appeared principally in the tubular epithelial cells, but not in the interstitial cells, thereby indicating that ROS is harmful in tubule cells, but is not in interstitial cells. In conclusion, ROS generated after I/R injury in cell proliferation and death performs a cell-type-specific and concentration-dependent role, even within the same tissues, and timely intervention of ROS is crucial for effective therapies.
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Ryuzaki, Masaki, Hirobumi Tokuyama, Kiyotaka Uchiyama, Hideaki Nakaya, Kazuhiro Hasegawa, Kazutoshi Miyashita, Kohnosuke Konishi, Akinori Hashiguchi, Shu Wakino, and Hiroshi Itoh. "Acute Interstitial Nephritis With Karyomegalic Epithelial Cells After Nivolumab Treatment—Two Case Reports." Clinical Medicine Insights: Case Reports 12 (January 2019): 117954761985364. http://dx.doi.org/10.1177/1179547619853647.
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Clinical application of immune checkpoint inhibitors (CPIs) including nivolumab is expanding in the field of oncology treatment. Nivolumab is an anti-programmed death 1 protein (PD-1) antibody designed to augment an immunologic reaction against cancer cells. On the contrary, CPIs are known to cause a unique variety of side effects termed as immune-related adverse events, which can affect any organ including kidney. However, the characteristics of renal disorders by nivolumab treatment are poorly described. We describe two cases of acute kidney injury that were treated with nivolumab. Two patients, one with renal-cell carcinoma and the other with lung cancer, exhibited progressive renal dysfunction after the initiation of nivolumab treatment. By kidney biopsy, each case was diagnosed as acute interstitial nephritis (AIN). Of note, tubular epithelial cells enlarged with hyperchromatic nuclei were focally observed, and this finding was consistent with karyomegalic tubular epithelial cells. In immunostaining, most of the enlarged tubular epithelial cells were positive for Ki-67, which suggested regeneration of tubular epithelial cells. Clinically, in one case, renal function was partially recovered with the discontinuation of nivolumab, while in another case renal function was fully recovered with additional corticosteroid treatment. We presented nivolumab-induced AIN with karyomegalic changes of tubular epithelia. We propose that immunosuppressive therapy may be necessary for the full recovery from renal impairment.
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Chen, Dong, Zhiyong Chen, Yuning Zhang, Chanyoung Park, Ahmed Al-Omari, and Gilbert W. Moeckel. "Role of medullary progenitor cells in epithelial cell migration and proliferation." American Journal of Physiology-Renal Physiology 307, no. 1 (July 1, 2014): F64—F74. http://dx.doi.org/10.1152/ajprenal.00547.2013.
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This study is aimed at characterizing medullary interstitial progenitor cells and to examine their capacity to induce tubular epithelial cell migration and proliferation. We have isolated a progenitor cell side population from a primary medullary interstitial cell line. We show that the medullary progenitor cells (MPCs) express CD24, CD44, CXCR7, CXCR4, nestin, and PAX7. MPCs are CD34 negative, which indicates that they are not bone marrow-derived stem cells. MPCs survive >50 passages, and when grown in epithelial differentiation medium develop phenotypic characteristics of epithelial cells. Inner medulla collecting duct (IMCD3) cells treated with conditioned medium from MPCs show significantly accelerated cell proliferation and migration. Conditioned medium from PGE2-treated MPCs induce tubule formation in IMCD3 cells grown in 3D Matrigel. Moreover, most of the MPCs express the pericyte marker PDGFR-b. Our study shows that the medullary interstitium harbors a side population of progenitor cells that can differentiate to epithelial cells and can stimulate tubular epithelial cell migration and proliferation. The findings of this study suggest that medullary pericyte/progenitor cells may play a critical role in collecting duct cell injury repair.
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Kato, Takashi, Man Hagiyama, Yasutoshi Takashima, Azusa Yoneshige, and Akihiko Ito. "Cell adhesion molecule-1 shedding induces apoptosis of renal epithelial cells and exacerbates human nephropathies." American Journal of Physiology-Renal Physiology 314, no. 3 (March 1, 2018): F388—F398. http://dx.doi.org/10.1152/ajprenal.00385.2017.
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Chronic kidney disease (CKD) is an important problem throughout the world, associated with the increase of blood urea nitrogen (BUN) and serum creatinine (sCre) and with renal tubular injuries. It is crucial to elucidate the molecular mechanisms of renal injuries to identify the new therapeutics and early diagnostic methods. We focused on cell adhesion molecule-1 (CADM1) protein. CADM1, its isoform SP4, is expressed in the epithelial cells of various tissues, including renal distal tubules, localized on the lateral cell membrane, mediates cell-cell adhesion via trans-homophilic binding, and interacts with various proteins. We previously reported that its expression was downregulated by post-proteolytic cleavage (α- and β-shedding) in pulmonary diseases. To investigate whether CADM1 α-shedding occurs in human nephropathies, we performed Western blotting and immunohistochemical analysis of specimens with arterionephrosclerosis (AS) and diabetic nephropathy (DN) from autopsied kidneys. CADM1 α-shedding was induced in AS and DN kidneys and derived from the decrease in full-length CADM1 (FL-CADM1) and increase of the COOH-terminal fragment (α-CTF). In particular, the reduced FL-CADM1 level was correlated with tubular and tubulointerstitial injuries and the increases in BUN and sCre levels. Apoptosis of renal tubular epithelial cells (TECs) was promoted in both nephropathies, and it was significantly correlated with the decrease in the FL-CADM1. Furthermore, FL-CADM1 knockdown by small interfering RNA downregulated anti-apoptotic Bcl-2 protein and promoted apoptosis of cultured renal TECs. The present study suggests that the reduction of FL-CADM1 leads to renal TEC apoptosis and could exacerbate renal tubular and tubulointerstitial injuries, which contribute to the development of CKD.
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Miao, Naijun, Bao Wang, Dan Xu, Yanzhe Wang, Xinxin Gan, Li Zhou, Hong Xue, Wei Zhang, Xiaoxia Wang, and Limin Lu. "Caspase-11 promotes cisplatin-induced renal tubular apoptosis through a caspase-3-dependent pathway." American Journal of Physiology-Renal Physiology 314, no. 2 (February 1, 2018): F269—F279. http://dx.doi.org/10.1152/ajprenal.00091.2017.
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Renal tubular injury is the hallmark of cisplatin-induced nephrotoxicity. Caspase-11, a member of the caspase family, plays an important role in inflammation and cell death. However, its role in cisplatin-induced renal tubular injury remains unclear. In cisplatin-treated mice, caspase-11 expression was significantly elevated and the expression of caspase-11 was mainly located in renal tubule. Inhibition of caspase-11 by small-interference RNA or its inhibitor wedelolactone attenuated cisplatin-induced renal dysfunction and tubular injury. In cultured primary renal tubular epithelial cells, cisplatin significantly promoted the expression and activation of caspase-11. Inhibition of caspase-11 by small-interference RNA reduced cisplatin-induced cell apoptosis. Overexpression of caspase-11 promoted cell apoptosis by activating the caspase-3-related cell apoptosis. Furthermore, coimmunoprecipitation results showed there was a direct interaction between caspase-11 and caspase-3, and the interaction was enhanced by cisplatin. The fluorescence confocal microscopy results showed that caspase-11 and caspase-3 were colocalized in the cytoplasm of renal tubular epithelial cells. These results demonstrate that caspase-11 plays an important role in cisplatin-induced renal tubular injury. Caspase-11 promotes renal epithelial cell apoptosis by activating the caspase-3-dependent apoptotic pathway. Caspase-11 might be a potential target for therapeutic treatment against cisplatin-induced nephrotoxicity.
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Nadasdy, T., Z. Laszik, K. E. Blick, L. D. Johnson, and F. G. Silva. "Proliferative activity of intrinsic cell populations in the normal human kidney." Journal of the American Society of Nephrology 4, no. 12 (June 1994): 2032–39. http://dx.doi.org/10.1681/asn.v4122032.
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The proliferative activity of various normal human renal cell populations is unknown. Recently, antibodies to cell proliferation-associated nuclear proteins, such as proliferating cell nuclear antigen (PCNA) and KI-67, which are applicable to archival paraffin sections, became available. With antibodies to PCNA and Ki-67 after microwave pretreatment of the paraffin sections, the proliferation indexes (ratio of positive nuclei with PCNA and Ki-67 antibodies/all nuclei counted x 100, i.e. percentage of positive cells) of 12 different intrinsic renal cell populations in 20 normal human kidneys have been determined. The following proliferation indexes (percentages of positive cells) were found with the PCNA and the Ki-67 antibodies, respectively: proximal tubular epithelium, 0.22, 0.24; thin limb of Henle, 0.29, 0.30; thick ascending limb of Henle, 0.32, 0.29; distal tubular epithelium (distal convoluted tubules and cortical collecting ducts, 0.33, 0.44; medullary collecting ducts, 0.32, 0.3; glomerular mesangial cells, 0.07, 0.12; glomerular visceral epithelial cells, 0.04, 0.08; glomerular parietal epithelial cells, 0.07, 0.1; glomerular capillary endothelium, 0.42, 0.47; peritubular capillary endothelial cells, 0.38, 0.43; endothelium of large intrarenal vessels (arteries and veins), 0.09, 0.12. Thus, normally capillary endothelium (glomerular and peritubular) appears to have the highest proliferation index in the human kidney by these techniques. These results indicate major variation in the proliferative activity of normal human renal cell populations, along with a significant correlation between PCNA and Ki-67 staining. Furthermore, this study provides normal values for the proliferative activity of different human renal cell populations.(ABSTRACT TRUNCATED AT 250 WORDS)
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Sorokin, L., A. Sonnenberg, M. Aumailley, R. Timpl, and P. Ekblom. "Recognition of the laminin E8 cell-binding site by an integrin possessing the alpha 6 subunit is essential for epithelial polarization in developing kidney tubules." Journal of Cell Biology 111, no. 3 (September 1, 1990): 1265–73. http://dx.doi.org/10.1083/jcb.111.3.1265.
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It has been previously shown that A-chain and domain(E8)-specific antibodies to laminin that inhibit cell adhesion also interfere with the establishment of epithelial cell polarity during kidney tubule development (Klein, G., M. Langegger, R. Timpl, and P. Ekblom. 1988. Cell. 55:331-341). A monoclonal antibody specific for the integrin alpha 6 subunit, which selectively blocks cell binding to E8, was used to study the receptors involved. Immunofluorescence staining of embryonic kidneys and of organ cultures of metanephric mesenchyme demonstrated coappearance of the integrin alpha 6 subunit and the laminin A-chain in regions where nonpolarized mesenchymal cells convert into polarized epithelial cells. Both epitopes showed marked colocalization in basal areas of tubules, while an exclusive immunostaining for alpha 6 was observed in lateral and apical cell surfaces of the tubular epithelial cells. Organ culture studies demonstrated a consistent inhibition of kidney epithelium development by antibodies against the alpha 6 subunit. The data suggest that the recognition of E8 cell-binding site of laminin by a specific integrin is crucial for the formation of kidney tubule epithelium from undifferentiated mesenchymal stem cells. In some other cell types (endothelium, some ureter cells) an exclusive expression of alpha 6 with no apparent colocalization of laminin A-chain in the corresponding basement membrane was seen. Thus, in these cells, integrins possessing the alpha 6 subunit may bind to laminin isoforms that differ from those synthesized by developing tubules.
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Guan, Yu, Daisuke Nakano, Lei Li, Haofeng Zheng, Akira Nishiyama, Ye Tian, and Lei Zhang. "Protease-Activated Receptor 1 Contributes to Microcirculation Failure and Tubular Damage in Renal Ischemia-Reperfusion Injury in Mice." BioMed Research International 2021 (February 23, 2021): 1–8. http://dx.doi.org/10.1155/2021/6665714.
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Ischemia-reperfusion- (IR-) induced kidney injury is difficult to avoid during renal transplantation and robot-assisted partial nephrectomy. Renal IR injury is characterized by tubular damage, microcirculation failure, and inflammation, which coordinately augment renal injury; however, no specific treatment is available for these conditions. Protease-activated receptor-1 (PAR-1) and its ligand, thrombin, are involved in coagulation and were shown to be associated with epithelial cell injury. Here, we hypothesized that PAR-1 exaggerated renal IR-induced tubular cell damage and microcirculation failure and that pharmacological inhibition of PAR-1 by Q94 could prevent these injuries. Renal warm IR increased the expression of PAR-1 in the renal tubules. Q94 attenuated renal IR-induced changes and histopathological damage. Microcirculation failure analyzed by congestion in the histopathology and blood cell flow examined by intravital multiphoton microscopy were suppressed by Q94 treatment. Q94 also dramatically increased tubular cell proliferation despite the lower renal damage. Thrombin suppressed cell proliferation and induced apoptosis in the tubules; these effects were prevented by Q94 treatment. Taken together, PAR-1 was associated with renal IR injury. Inhibition of PAR-1 ameliorated injury possibly by improving renal microcirculation and tubular cell survival/proliferation.
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Wu, Chia-Lin, Chia-Chu Chang, Tao-Hsiang Yang, Alexander Charng-Dar Tsai, Jui-Lin Wang, Chung-Ho Chang, and Der-Cherng Tarng. "Tubular transcriptional co-activator with PDZ-binding motif protects against ischemic acute kidney injury." Clinical Science 134, no. 13 (June 30, 2020): 1593–612. http://dx.doi.org/10.1042/cs20200223.
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Abstract Transcriptional co-activator with PDZ-binding motif (TAZ) is a key downstream effector of the Hippo tumor-suppressor pathway. The functions of TAZ in the kidney, especially in tubular epithelial cells, are not well-known. To elucidate the adaptive expression, protective effects on kidney injury, and signaling pathways of TAZ in response to acute kidney injury (AKI), we used in vitro (hypoxia-treated human renal proximal tubular epithelial cells [RPTECs]) and in vivo (mouse ischemia–reperfusion injury [IRI]) models of ischemic AKI. After ischemic AKI, TAZ was up-regulated in RPTECs and the renal cortex or tubules. Up-regulation of TAZ in RPTECs subjected to hypoxia was controlled by IκB kinase (IKK)/nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling. TAZ overexpression attenuated hypoxic and oxidative injury, inhibited apoptosis and activation of p38 and c-Jun N-terminal kinase (JNK) proteins, and promoted wound healing in an RPTEC monolayer. However, TAZ knockdown aggravated hypoxic injury, apoptosis, and activation of p38 and JNK signaling, delayed wound closure of an RPTEC monolayer, and promoted G0/G1 phase cell-cycle arrest. Chloroquine and verteporfin treatment produced similar results to TAZ overexpression and knockdown in RPTECs, respectively. Compared with vehicle-treated mice, chloroquine treatment increased TAZ in the renal cortex and tubules, improved renal function, and attenuated tubular injury and tubular apoptosis after renal IRI, whereas TAZ siRNA and verteporfin decreased TAZ in the renal cortex and tubules, deteriorated renal failure and tubular injury, and aggravated tubular apoptosis. Our findings indicate the renoprotective role of tubular TAZ in ischemic AKI. Drugs augmenting (e.g., chloroquine) or suppressing (e.g., verteporfin) TAZ in the kidney might be beneficial or deleterious to patients with AKI.
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Demmers, M. W. H. J., S. S. Korevaar, M. Roemeling-van Rhijn, T. P. P. van den Bosch, M. J. Hoogduijn, M. G. H. Betjes, W. Weimar, C. C. Baan, and A. T. Rowshani. "Human renal tubular epithelial cells suppress alloreactive T cell proliferation." Clinical & Experimental Immunology 179, no. 3 (February 16, 2015): 509–19. http://dx.doi.org/10.1111/cei.12469.
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Ichimura, T., P. W. Finch, G. Zhang, M. Kan, and J. L. Stevens. "Induction of FGF-7 after kidney damage: a possible paracrine mechanism for tubule repair." American Journal of Physiology-Renal Physiology 271, no. 5 (November 1, 1996): F967—F976. http://dx.doi.org/10.1152/ajprenal.1996.271.5.f967.
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A member of the fibroblast growth factor (FGF) family, keratinocyte growth factor (FGF-7 has unique specificity for epithelial cells. We investigated the role of FGF-7 in repair of proximal tubular damage caused by S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC). In situ hybridization localized FGF-7 to interstitial cells in the medulla and outer stripe of the outer medulla. Interstitial FGF-7 expression increased throughout the kidney 1 day after TFEC treatment. FGFR2 IIIb mRNA was high in the papilla and medulla and also increased after TFEC administration. By in situ hybridization, FGFR2 IIIb was localized to the tubular epithelium, particularly in collecting ducts. Proliferation of collecting duct epithelial cells increased in adult kidney after damage to the proximal tubule. FGFR2 IIIb, but not FGF-7, mRNA was also expressed by rat proximal tubule epithelial (RPTE) cells in vitro, and FGF-7 increased DNA synthesis in RPTE. Thus FGFR2 IIIb and FGF-7 expression is segregated between epithelial and interstitial cells forming a paracrine growth factor loop. These results raise the possibility that a novel paracrine growth loop is activated by chemical damage and regulates epithelial cell growth during tubular repair.
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Schreiber, Pamela, Ann-Kathrin Friedrich, Gefion Gruber, Christian Nusshag, Lukas Boegelein, Sandra Essbauer, Josephine Uhrig, Martin Zeier, and Ellen Krautkrämer. "Differences in the Susceptibility of Human Tubular Epithelial Cells for Infection with Orthohantaviruses." Viruses 15, no. 8 (July 31, 2023): 1670. http://dx.doi.org/10.3390/v15081670.
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Diseases induced by infection with pathogenic orthohantaviruses are characterized by a pronounced organ-specific manifestation. Pathogenic Eurasian orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS) with often massive proteinuria. Therefore, the use of a relevant kidney cell culture would be favorable to analyze the underlying cellular mechanisms of orthohantavirus-induced acute kidney injury (AKI). We tested different human tubular epithelial cell lines for their suitability as an in vitro infection model. Permissiveness and replication kinetics of highly pathogenic Hantaan virus (HTNV) and non-/low-pathogenic Tula virus (TULV) were analyzed in tubular epithelial cell lines and compared to human primary tubular epithelial cells. Ana-lysis of the cell line HK-2 revealed the same results for viral replication, morphological and functional effects as observed for HTNV in primary cells. In contrast, the cell lines RPTEC/TERT1 and TH1 demonstrated only poor infection rates after inoculation with HTNV and are unusable as an infection model. While pathogenic HNTV infects primary tubular and HK-2 cells, non-/low-pathogenic TULV infects neither primary tubular cells nor the cell line HK-2. Our results show that permissiveness of renal cells varies between orthohantaviruses with differences in pathogenicity and that HK-2 cells demonstrate a suitable in vitro model to study viral tropism and pathogenesis of orthohantavirus-induced AKI.
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Bakker, R. C. "Renal tubular epithelial cell death and cyclosporin A." Nephrology Dialysis Transplantation 17, no. 7 (July 1, 2002): 1181–88. http://dx.doi.org/10.1093/ndt/17.7.1181.
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Sant, Snehal, Dan Wang, and Nicholas J. Ferrell. "Stiffening of Decellularized Tubular Basement Membrane Regulates Renal Tubular Epithelial Cell Function." Journal of the American Society of Nephrology 31, no. 10S (October 2020): 146. http://dx.doi.org/10.1681/asn.20203110s1146b.
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Li, Z.-D., X.-L. Zhang, N. Yi, and F.-C. Zhang. "Elimination of etimicin in rat kidneys and alterations of its cytotoxicity to tubular epithelial cells." Human & Experimental Toxicology 34, no. 5 (September 17, 2014): 479–86. http://dx.doi.org/10.1177/0960327114550887.
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Etimicin (ETM) can accumulate in kidneys and cause tubular epithelial cell cytotoxicity. This article aims to study ETM elimination in kidneys and its nephrotoxicity, apoptosis, and histopathological insults of renal tubular epithelial cells, after repeated administration. A total of 36 rats were randomly divided into ETM-treated group and vehicle control group. Rats in ETM-treated group were treated intraperitoneally (i.p.) with 100 mg/kg/day ETM and rats in control group received physiological saline (i.p.) for 5 consecutive days. Determination of ETM concentrations accumulated in rat kidneys was carried out by high-performance liquid chromatography on the basis of derivatization with o-phthalaldehyde and by ultraviolet detector. Apoptotic renal tubular epithelial cells were identified by a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay. Histopathological insults in kidneys were evaluated by hematoxylin and eosin staining. On day 1 after cessation of ETM administration, the accumulation concentration was 347.50 ± 193.30 μg/g tissue; on day 15, ETM concentration became 16.71 ± 9.99 μg/g tissue. Elimination half-life of ETM in rat kidney was about 3.05 days. Apoptotic renal tubular epithelial cells induced by etimicin was recovered gradually from 1544 ± 138 n/mm2 on day 1 to 716 ± 208 n/mm2 on day 15. Histopathological damage was also gradually recovered from vacuolation of tubular epithelial cells as well as renal tubular edema on days 1, 3, and 7 to nearly normal on day 15. From these results, we concluded that renal tubular epithelial cell cytotoxicity induced by ETM can gradually restore with its decreasing concentration in rat kidneys.