Journal articles on the topic 'Tubular regeneration'
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Ichimura, T., J. A. Maier, T. Maciag, G. Zhang, and J. L. Stevens. "FGF-1 in normal and regenerating kidney: expression in mononuclear, interstitial, and regenerating epithelial cells." American Journal of Physiology-Renal Physiology 269, no. 5 (November 1, 1995): F653—F662. http://dx.doi.org/10.1152/ajprenal.1995.269.5.f653.
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The proximal tubule epithelium regenerates following nephrotoxic damage. To determine the role of fibroblast growth factors (FGFs) in the regeneration of rat proximal tubule epithelial (RPTE) cells, we investigated proliferation, differentiation, and FGF-1 expression in vivo in rat kidney before and after nephrotoxic damage to the proximal tubule epithelium caused by S-(1,1,2,2-tetrafluoroethyl)-L-cysteine administration. In undamaged kidneys, FGF-1 was expressed in distal tubule elements, including cortical and medullary collecting ducts, as well as in blood vessels and glomeruli, but was absent in RPTE. One day after damage, there was an increase in proliferation of surviving proximal tubule epithelial cells and a coincident increase in FGF-1 expression in invading mononuclear cells. After this initial burst of proliferation, FGF-1 expression increased in poorly differentiated vimentin-positive regenerative epithelial cells, indicating that autocrine FGF-1 expression in the regenerative epithelium is a later event in the regeneration process. FGF-1 staining persisted in foci of macrophages, interstitial cells, and nephropathic tubules within areas of interstitial expansion 2 wk after damage. We concluded that transient paracrine and autocrine expression of FGF-1 could play mitogenic and/or morphogenic roles during tubular regeneration. Persistent expression in macrophages, fibroblasts, and nephropathic tubules may be associated with tubular degeneration. FGF-1 expression may be an important contributor to both tubular regeneration and degenerative disease following toxicant exposure.
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Maeshima, Akito, Shunsuke Takahashi, Masao Nakasatomi, and Yoshihisa Nojima. "Diverse Cell Populations Involved in Regeneration of Renal Tubular Epithelium following Acute Kidney Injury." Stem Cells International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/964849.
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Renal tubular epithelium has the capacity to regenerate, repair, and reepithelialize in response to a variety of insults. Previous studies with several kidney injury models demonstrated that various growth factors, transcription factors, and extracellular matrices are involved in this process. Surviving tubular cells actively proliferate, migrate, and differentiate in the kidney regeneration process after injury, and some cells express putative stem cell markers or possess stem cell properties. Using fate mapping techniques, bone marrow-derived cells and endothelial progenitor cells have been shown to transdifferentiate into tubular components in vivo or ex vivo. Similarly, it has been demonstrated that, during tubular cell regeneration, several inflammatory cell populations migrate, assemble around tubular cells, and interact with tubular cells during the repair of tubular epithelium. In this review, we describe recent advances in understanding the regeneration mechanisms of renal tubules, particularly the characteristics of various cell populations contributing to tubular regeneration, and highlight the targets for the development of regenerative medicine for treating kidney diseases in humans.
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Mangione, F., G. Mazzucco, and A. D. Canton. "Tubular regeneration." Clinical Kidney Journal 1, no. 1 (December 19, 2007): 51–52. http://dx.doi.org/10.1093/ndtplus/sfm007.
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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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Padanilam, B. J., and M. R. Hammerman. "Ischemia-induced receptor for activated C kinase (RACK1) expression in rat kidneys." American Journal of Physiology-Renal Physiology 272, no. 2 (February 1, 1997): F160—F166. http://dx.doi.org/10.1152/ajprenal.1997.272.2.f160.
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Differential display-polymerase chain reaction (DD-PCR) was used to identify genes that are expressed in kidney following induction of acute ischemic renal injury. The receptor for activated C kinase (RACK1) mRNA expression in kidneys obtained from rats 12 h following ischemia is enhanced twofold compared with sham-operated rats. The maximal enhancement of expression (3.3-fold) is at 7 days following reperfusion. Expression remains elevated at 14 days. RACK1 transcripts and protein are localized to the damaged and regenerating segments of proximal tubules. At 1 day following injury, RACK1 protein is present in the epithelial cells of the damaged S3 segment and in cells sloughed into the tubular lumen. By 5 days following injury, RACK1 protein expression is enhanced in the regenerating cells relining the injured tubules of the S3 segment and in papillary proliferations within regenerating tubules. Increased expression of RACK1 could enhance the activity of PKC and, in so doing, regulate the process of regeneration of the proximal tubule following ischemic renal injury.
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Moreno, Juan Carlos Alvarez, Hisham F. Bahmad, Christopher A. Febres-Aldana, Andrés Pirela, Andres Azuero, Ali Salami, and Robert Poppiti. "Post-mortem assessment of vimentin expression as a biomarker for renal tubular regeneration following acute kidney injury." Journal of Pathology and Translational Medicine 55, no. 6 (November 15, 2021): 369–79. http://dx.doi.org/10.4132/jptm.2021.08.03.
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Background: Acute kidney injury (AKI) is a common cause of morbidity and mortality. It mainly targets the renal tubular epithelium with pathological changes, referred to as acute tubular injury. The latter is followed by a regenerative response that is difficult to visualize on routine hematoxylin and eosin (H&E) stains. In this study, we examined the regenerative capacity of renal tubules by correlating vimentin (VIM) immunohistochemical (IHC) expression and pathological findings of AKI and renal tubular regeneration (RTR) on H&E.Methods: We reviewed 23 autopsies performed in the clinical setting of AKI and RTR. VIM expression was scored in the renal cortical tubular epithelium using a statistical cutoff ≥ 3% for high expression and < 3% for low expression.Results: Of the 23 kidney tissues examined, seven (30.4%) had low VIM expression, and 16 (69.6%) had high VIM expression. Kidney tissues with evidence of AKI and RTR had significantly higher VIM expression. Renal peritubular microenvironment features showing regenerative changes on H&E were associated with high VIM expression. In the univariate model, kidney tissues with RTR were 18-fold more likely to have high VIM expression.Conclusions: In conclusion, our findings suggest that VIM could serve as an IHC marker for RTR following AKI. However, correlation with H&E findings remains critical to excluding chronic tubular damage. Collectively, our preliminary results pave the way for future studies including a larger sample size to validate the use of VIM as a reliable biomarker for RTR.
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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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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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Amuthan, Arul, Vasudha Devi, Chandrashekara Shastry Shreedhara, Venkata Rao, Kunal Puri, and Shiny Jasphin. "VERNONIA CINEREA (NEICHITTI KEERAI) REGENERATES PROXIMAL TUBULES IN CISPLATININDUCED RENAL DAMAGE IN MICE." Asian Journal of Pharmaceutical and Clinical Research 12, no. 1 (January 7, 2019): 332. http://dx.doi.org/10.22159/ajpcr.2018.v12i1.27464.
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Objective: The aim of the study was to evaluate whether Vernonia cinerea (VC) regenerates the proximal renal tubular cells in cisplatin-induced necrosis in male Swiss albino mice.Methods: The crude aqueous extract (CAE) of VC was fractionated from non-polar to polar using different solvents. Mice were injected a single dose of cisplatin (15 mg/kg) on day 1, which took 5 days to cause maximal renal damage. From day 6, CAE and all fractions were orally administered (200, 300, and 400 mg/kg) for 5 continuous days. On day 11, blood was collected to estimate urea and creatinine. Kidney was collected for histology and grading was done.Results: Cisplatin induced proximal renal tubular damage (grade 5) in corticomedullary junction, characterized by necrosis, proximal tubular dilatation, inflammation and vasodilation. Aqueous fraction (AF) did not show any regeneration; whereas, 400 mg/kg dose of CAE and butanol fraction (BF) showed a significant reduction (p<0.001) in proximal tubular damage (Grade 3) and 50–75% regeneration of proximal tubular epithelial cells.Conclusion: This is the first study to demonstrate the regenerative potential of Neichitti kashayam (CAE of VC) and its BF in cisplatin-induced proximal tubular damage in kidney. Further study is warranted to find out the dose regimen for complete regeneration, lead compounds, and molecular mechanism.
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Amuthan, Arul, Vasudha Devi, Chandrashekara Shastry Shreedhara, Venkata Rao, Kunal Puri, and Shiny Jasphin. "VERNONIA CINEREA (NEICHITTI KEERAI) REGENERATES PROXIMAL TUBULES IN CISPLATININDUCED RENAL DAMAGE IN MICE." Asian Journal of Pharmaceutical and Clinical Research 12, no. 1 (January 7, 2019): 332. http://dx.doi.org/10.22159/ajpcr.2019.v12i1.27464.
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Objective: The aim of the study was to evaluate whether Vernonia cinerea (VC) regenerates the proximal renal tubular cells in cisplatin-induced necrosis in male Swiss albino mice.Methods: The crude aqueous extract (CAE) of VC was fractionated from non-polar to polar using different solvents. Mice were injected a single dose of cisplatin (15 mg/kg) on day 1, which took 5 days to cause maximal renal damage. From day 6, CAE and all fractions were orally administered (200, 300, and 400 mg/kg) for 5 continuous days. On day 11, blood was collected to estimate urea and creatinine. Kidney was collected for histology and grading was done.Results: Cisplatin induced proximal renal tubular damage (grade 5) in corticomedullary junction, characterized by necrosis, proximal tubular dilatation, inflammation and vasodilation. Aqueous fraction (AF) did not show any regeneration; whereas, 400 mg/kg dose of CAE and butanol fraction (BF) showed a significant reduction (p<0.001) in proximal tubular damage (Grade 3) and 50–75% regeneration of proximal tubular epithelial cells.Conclusion: This is the first study to demonstrate the regenerative potential of Neichitti kashayam (CAE of VC) and its BF in cisplatin-induced proximal tubular damage in kidney. Further study is warranted to find out the dose regimen for complete regeneration, lead compounds, and molecular mechanism.
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Toback, F. Gary. "Regeneration after acute tubular necrosis." Kidney International 41, no. 1 (January 1992): 226–46. http://dx.doi.org/10.1038/ki.1992.32.
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Piron, Annie, Isabelle Leonard, Denis Nonclercq, Gerard Toubeau, Paul Falmagne, Jeanine-Anne Heuson-Stiennon, and Guy Laurent. "In vitro demonstration of a mitogenic activity in renal tissue extracts during regenerative hyperplasia." American Journal of Physiology-Renal Physiology 274, no. 2 (February 1, 1998): F348—F357. http://dx.doi.org/10.1152/ajprenal.1998.274.2.f348.
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Normal rat kidney (NRK-52E) cells, an established cell line of renal origin, were used as a bioassay system to reveal a possible mitogenic activity in tissue extracts prepared from kidneys undergoing tubular regeneration. Acute tubular injury was induced in female Wistar rats by a 4-day treatment with gentamicin at daily doses of 50 or 100 mg/kg twice daily. Animals were killed either 1 or 4 days after cessation of gentamicin administration. Proximal tubule regeneration in treated animals was confirmed by morphological examination after proliferating cell nuclear antigen staining. Tissue extracts from regenerating kidneys stimulated DNA synthesis in growth-arrested cells to a higher extent than extracts from intact kidneys. Sera from treated and control animals showed no difference with respect to mitogenic activity. The mitogenic effect of tissue extracts was sensitive to the tyrosine kinase inhibitor tyrphostin A46. The cell proliferative response to regenerating kidney extracts, but not that to intact kidney extracts, was partly suppressed by the addition of anti-insulin-like growth factor I (anti-IGF-I) antiserum. These data indicate that nephrogenic repair entails an elevation of biologically active IGF-I in kidney tissue.
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Basu, Joydeep, and John W. Ludlow. "Platform technologies for tubular organ regeneration." Trends in Biotechnology 28, no. 10 (October 2010): 526–33. http://dx.doi.org/10.1016/j.tibtech.2010.07.007.
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Fields, R. Douglas, Jean M. Le Beau, Frank M. Longo, and Mark H. Ellisman. "Nerve regeneration through artificial tubular implants." Progress in Neurobiology 33, no. 2 (January 1989): 87–134. http://dx.doi.org/10.1016/0301-0082(89)90036-1.
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McDuffie, James Eric, Jing Ying Ma, Marciano Sablad, Manisha Sonee, Lynn Varacallo, Calvert Louden, Antonio Guy, et al. "Time Course of Renal Proximal Tubule Injury, Reversal, and Related Biomarker Changes in Rats Following Cisplatin Administration." International Journal of Toxicology 32, no. 4 (June 20, 2013): 251–60. http://dx.doi.org/10.1177/1091581813493013.
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Cisplatin (CDDP) is known to produce renal proximal tubule injury. Various renal biomarkers have been related to CDDP nephrotoxicity in previous research, but the temporal and spatial relationship of these biomarkers to injury reversal has not been well defined. In this study, the progression and reversal of renal histopathology findings relative to serum and urinary biomarker changes were examined during a 4-week postdose period following single intraperitoneal administration of CDDP (1 mg/kg) or 0.9% saline. Degeneration, vacuolation, inflammation, and regeneration of the S3 segment of proximal tubules were evident 72 hours following CDDP administration. Tubular degeneration and regeneration were also observed at 1 and 1.5 weeks but at lower incidences and/or severity indicating partial reversal. Complete histologic reversal was observed by 2 weeks following CDDP administration. Urinary kidney injury molecule 1 (KIM-1), α-glutathione-S-transferase (α-GST), and albumin levels increased at 72 hours postdosing, concurrently with the earliest histologic evidence of tubule injury. Changes in urinary KIM-1 correlated with KIM-1 immunostaining in the proximal tubular epithelial cells. No significant changes in serum biomarkers occurred except for a minimal increase in urea nitrogen at 1.5 weeks postdosing. Of the novel renal biomarkers examined, urinary KIM-1, α-GST, and albumin showed excellent concordance with CDDP-induced renal injury progression and reversal; and these biomarkers were more sensitive than traditional serum biomarkers in detecting early, acute renal tubular damage confirmed by histopathology. Furthermore, urinary KIM-1, α-GST, and albumin outperformed other biomarkers in correlating with the time of maximum histologic injury.
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MAESHIMA, AKITO, YOU-QING ZHANG, YOSHIHISA NOJIMA, TAKUJI NARUSE, and ITARU KOJIMA. "Involvement of the Activin-Follistatin System in Tubular Regeneration after Renal Ischemia in Rats." Journal of the American Society of Nephrology 12, no. 8 (August 2001): 1685–95. http://dx.doi.org/10.1681/asn.v1281685.
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Abstract. This study was conducted to investigate the involvement of the activin-follistatin system in renal regeneration after ischemic injury. Expression of mRNA for the activin βA subunit was not detected in normal kidneys but increased markedly after renal ischemia. Immunoreactive βA subunit was detected in tubular cells of the outer medulla in ischemic but not normal kidneys. Expression of mRNA for follistatin, an antagonist of activin A, was abundant in tubular cells of the outer medulla in normal kidneys and decreased significantly after renal ischemia. For assessment of the role of the activin-follistatin system in renal regeneration after ischemic injury, recombinant follistatin was intravenously infused into rats with renal ischemia, at the time of reperfusion. Exogenous follistatin prevented the histologic changes induced by ischemic injury, reduced apoptosis in tubular cells, and accelerated tubular cell proliferation. Serum levels of creatinine and blood urea nitrogen were significantly lower in follistatin-treated rats. Conversely, intravenous administration of recombinant activin A inhibited tubular cell proliferation after ischemic injury. These results indicate that the activin-follistatin system participates in renal regeneration after ischemic injury. Follistatin administered intravenously accelerates renal regeneration after renal ischemia, presumably by blocking the actions of endogenous activin.
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Jamadar, Abeda, and Reena Rao. "Glycogen Synthase Kinase-3 Signaling in Acute Kidney Injury." Nephron 144, no. 12 (2020): 609–12. http://dx.doi.org/10.1159/000509354.
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Acute kidney injury (AKI) is a common clinical syndrome that involves renal tubular epithelial cell death and leads to acute decline in renal function. Improper tubular regeneration following AKI often leads to CKD. We discuss the role of a serine/threonine protein kinase called glycogen synthase kinase-3 (GSK3) in renal tubular injury and renal fibrosis. We also highlight the importance of GSK3 as a potential drug target in AKI patients and molecular mechanisms promoting tissue regeneration.
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Basile, D. P., J. M. Rovak, D. R. Martin, and M. R. Hammerman. "Increased transforming growth factor-beta 1 expression in regenerating rat renal tubules following ischemic injury." American Journal of Physiology-Renal Physiology 270, no. 3 (March 1, 1996): F500—F509. http://dx.doi.org/10.1152/ajprenal.1996.270.3.f500.
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To gain insight into the role that transforming growth factor-beta 1 (TGF-beta 1) plays in the regeneration of kidneys following acute renal failure, we characterized the expression of TGF-beta 1 mRNA and the expression of active and latent TGF-beta peptide at various times during recovery from acute ischemic injury in rat. Levels of whole kidney TGF-beta 1 mRNA were elevated significantly at 12 h postinjury (1.5-fold vs. sham-operated controls), and by 24 h postinjury were elevated by 3.6-fold. Levels remained elevated for 14 days following ischemia, but were no longer elevated at 28 days postinjury. In situ hybridization demonstrated that the elevated expression of TGF-beta 1 was localized predominantly to cells in the regenerating tubules in the outer medulla. When examined at 14 days postischemia, levels of TGF-beta 1 mRNA were elevated in the outer medulla only in tubules that appeared incompletely regenerated. Immunohistochemical staining localized active TGF-beta to the lumen of proximal tubules in control animals and in desquamated and regenerating tubular epithelial cells following ischemia. TGF-beta 1 latency-associated peptide was present intracellularly in proximal tubules of sham-operated rats and reduced following ischemia. We hypothesize that endogenous renal TGF-beta serves to promote tissue regeneration following acute injury via an autocrine or paracrine mechanism.
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Nakagawa, Shunsaku, Tomohiro Omura, Atsushi Yonezawa, Ikuko Yano, Takayuki Nakagawa, and Kazuo Matsubara. "Extracellular nucleotides from dying cells act as molecular signals to promote wound repair in renal tubular injury." American Journal of Physiology-Renal Physiology 307, no. 12 (December 15, 2014): F1404—F1411. http://dx.doi.org/10.1152/ajprenal.00196.2014.
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Acute kidney injury (AKI) often correlates with poor prognosis and is followed by various severe unfavorable systemic outcomes. It is important to understand the pathophysiology of AKI for the development of novel therapeutic approaches toward promoting renal regeneration after injury. Recent studies have indicated that AKI-induced tubular cell death plays an active role in the onset of tissue regeneration; however, the mechanisms underlying renal tubular repair after injury have yet to be understood. In the present study, we explored molecules that might serve as “danger” signals in mediating tubular regeneration. Kidneys of rats systemically administered the nephrotoxicant cisplatin (to induce AKI) exhibited massive cell proliferation. The proportion of proliferating cells in the total cell distribution was highest in the outer stripe of the outer medulla coincided with where the tubular damage was the most severe in this study. This finding suggests that soluble factors may have been released from damaged cells to stimulate the proliferation of neighboring tubular epithelial cells. In elucidating the mechanism of dying cell-to-surviving cell communication using normal rat kidney NRK-52E epithelial cells, we found a significant increase in ATP levels in supernatants of these cells after the induction of cell death using ultraviolet irradiation. Furthermore, treatment of conditioned supernatants with apyrase or suramin, which inhibits purinergic signaling, resulted in significant decreases in cell proliferation and migration activities. These results demonstrate a novel role for extracellular nucleotides, probably as danger signals in aggravating tubular regeneration after AKI.
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Selhub, J., S. Nakamura, and F. A. Carone. "Renal folate absorption and the kidney folate binding protein. II. Microinfusion studies." American Journal of Physiology-Renal Physiology 252, no. 4 (April 1, 1987): F757—F760. http://dx.doi.org/10.1152/ajprenal.1987.252.4.f757.
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Surface proximal convoluted tubules (PCT) in rats were microinfused in situ with [3H]folic acid to study the role of folate binding protein (FBP) in the kidney brush-border membrane for renal conservation and transport of folate [3H]folic acid absorption was linearly related to tubular length of PCT and occurred largely in this segment of the tubule. Unlabeled folate derivatives inhibited [3H]folic acid absorption, the extent of which was dependent on the type of unlabeled folate used and its concentration. At equivalent concentrations, inhibition was most effective with unlabeled folic acid, slightly lower than with 5-methyltetrahydrofolate and least effective with methotrexate. Comparisons between [3H]folic acid absorption before and after infusion of a saturating dose of unlabeled folic acid or repetitive injections of [3H]folic acid into the same tubular site revealed continuous and rapid regeneration of unsaturated folic acid uptake sites with an apparent half-life of 28.75 +/- 8.75 s. Determination of [3H] retained in the tubule at various periods after microinfusion of [3H]folic acid revealed slow cellular disappearance with an apparent half-life of 47.3 +/- 5.4 min. It is proposed that the brush-border FBP functions as a receptor of infused folic acid and that following the binding of the ligand the folic acid/FBP complex undergoes a rapid change that results in the internalization of folic acid and regeneration of unsaturated binding sites at the membrane surface. Internalized folic acid is slowly released into renal capillaries.
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Maremonti, Francesca, Claudia Meyer, and Andreas Linkermann. "Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss." Journal of the American Society of Nephrology 33, no. 3 (January 12, 2022): 472–86. http://dx.doi.org/10.1681/asn.2021101293.
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Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this “switch” must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.
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Dahlke, Eileen, Toni Engmann, Yaman Anan, Robert Häsler, Giovanni Solinas, and Franziska Theilig. "Tubular IKKβ Deletion Alleviates Acute Ischemic Kidney Injury and Facilitates Tissue Regeneration." International Journal of Molecular Sciences 23, no. 17 (September 5, 2022): 10199. http://dx.doi.org/10.3390/ijms231710199.
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Acute kidney injury (AKI) is a common renal injury leading to relevant morbidity and mortality worldwide. Most of the clinical cases of AKI are caused by ischemia reperfusion (I/R) injury with renal ischemia injury followed by reperfusion injury and activation of the innate immune response converging to NF-ĸB pathway induction. Despite the clear role of NF-ĸB in inflammation, it has recently been acknowledged that NF-ĸB may impact other cell functions. To identify NF-ĸB function with respect to metabolism, vascular function and oxidative stress after I/R injury and to decipher in detail the underlying mechanism, we generated a transgenic mouse model with targeted deletion of IKKβ along the tubule and applied I/R injury followed by its analysis after 2 and 14 days after I/R injury. Tubular IKKβ deletion ameliorated renal function and reduced tissue damage. RNAseq data together with immunohistochemical, biochemical and morphometric analysis demonstrated an ameliorated vascular organization and mRNA expression profile for increased angiogenesis in mice with tubular IKKβ deletion at 2 days after I/R injury. RNAseq and protein analysis indicate an ameliorated metabolism, oxidative species handling and timely-adapted cell proliferation and apoptosis as well as reduced fibrosis in mice with tubular IKKβ deletion at 14 days after I/R injury. In conclusion, mice with tubular IKKβ deletion upon I/R injury display improved renal function and reduced tissue damage and fibrosis in association with improved vascularization, metabolism, reactive species disposal and fine-tuned cell proliferation.
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Wen, Donghai, Li Ni, Li You, Liying Zhang, Yong Gu, Chuan-Ming Hao, and Jing Chen. "Upregulation of nestin in proximal tubules may participate in cell migration during renal repair." American Journal of Physiology-Renal Physiology 303, no. 11 (December 1, 2012): F1534—F1544. http://dx.doi.org/10.1152/ajprenal.00083.2012.
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The characteristics of renal tubular progenitor/precursor cells and the role of renal tubule regeneration in the repair of remnant kidneys (RKs) after nephrectomy are not well known. In the present study of a murine model of subtotal nephrectomy, we used immunofluorescence (IF), immunoblot analysis, and in situ hybridization methods to demonstrate that nestin expression was transiently upregulated in tubule cells near the incision edges of RKs. The nestin-positive tubules were immature proximal tubules that colabeled with lotus tetragonolobus agglutinin but not with markers of mature tubules (aquaporin-1, Tamm-Horsfall protein, and aquaporin-2). In addition, many of the nestin-expressing tubule cells were actively proliferative cells, as indicated by colabeling with bromodeoxyuridine. Double-label IF and immunoblot analysis also showed that the upregulation of tubular nestin was associated with enhanced transforming growth factor-β1 (TGF-β1) expression in the incision edge of RKs but not α-smooth muscle actin, which is a marker of fibrosis. In cultured human kidney proximal tubule cells (HKC), immunoblot analysis indicated that TGF-β1 induced nestin expression and loss of E-cadherin expression, suggesting an association of nestin expression and cellular dedifferentiation. Knockdown of nestin expression by a short hairpin RNA-containing plasmid led to decreased migration of HKC cells that were induced by TGF-β1. Taken together, our results suggest that the tubule repair that occurs during the recovery process following nephrectomy may involve TGF-β1-induced nestin expression in immature renal proximal tubule cells and the promotion of renal cell migration.
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Ogata, Koji, Yoshiko Shimamura, Kazu Hamada, Masayuki Hisa, Masayuki Bun, Nazuki Okada, Kosuke Inoue, et al. "Upregulation of HNF-1β during experimental acute kidney injury plays a crucial role in renal tubule regeneration." American Journal of Physiology-Renal Physiology 303, no. 5 (September 1, 2012): F689—F699. http://dx.doi.org/10.1152/ajprenal.00086.2012.
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Hepatocyte nuclear factor-1β (HNF-1β) is a transcription factor expressed in the kidney, liver, pancreas, and other organs. Mutations of HNF-1β cause maturity-onset diabetes of the young type 5 (MODY5). The aims of this study were to investigate the functional roles of the HNF-1β/suppressor of cytokine signaling-3 (SOCS-3) pathway in tubule damage after acute kidney injury (AKI) both in vivo and in vitro and to examine the effect of HNF-1β on renal tubule formation. To clarify the significance of the HNF-1β/SOCS-3 pathway in AKI, we used a rat ischemia/reperfusion (I/R) AKI model and cultured renal tubular cells (NRK-52E cells). Western blot analysis showed that HNF-1β and polycystic kidney disease 2 (PKD2) expressions were increased at 3–12 h and 12–24 h after I/R, respectively. The expression level of SOCS-3 was decreased at 3–48 h. Immunohistological examination revealed that expression of HNF-1β was increased in proximal tubules. Overexpression of HNF-1β resulted in decreased SOCS-3 expression, activation of signal transducer and activator of transcription 3 (STAT3) and Erk, and increased [3H]thymidine uptake in the presence of hepatocyte growth factor. Furthermore, tubule formation in three-dimensional gels was inhibited by dominant-negative HNF-1β. Our study shows that HNF-1β is upregulated after AKI in proximal tubular cells and that HNF-1β controls cellular proliferation and tubule formation by regulating SOCS-3 expression and STAT3/Erk activation. Therefore, the current study unravels the physiological and pathological significance of the HNF-1β pathway in AKI.
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Ochi, Akinobu, Dong Chen, Wibke Schulte, Lin Leng, Nickolas Moeckel, Marta Piecychna, Luisa Averdunk, Christian Stoppe, Richard Bucala, and Gilbert Moeckel. "MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms." American Journal of Physiology-Renal Physiology 313, no. 3 (September 1, 2017): F767—F780. http://dx.doi.org/10.1152/ajprenal.00683.2016.
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Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions that is produced by several organs and cell types. Depending on the target cell and the inflammatory context, MIF can engage its two component receptor complex CD74 and CD44 and the chemokine receptors CXCR2/4. MIF is constitutively expressed in renal proximal tubular cells, stored in intracellular preformed pools, and released at a low rate. Recently, a second MIF-like protein (i.e., MIF-2/D-DT) has been characterized in mammals. Our study was aimed at examining the role of MIF-2/D-DT, which mediates tissue protection in the heart, in tubular cell regeneration from ischemia-reperfusion injury. We found that Mif−/−, Mif-2−/−, and Cd74−/− mice had significantly worse tubular injury compared with wild-type (WT) control mice and that treatment with MIF-2/D-DT significantly improved recovery of injured epithelial cells. RNAseq analysis of kidney tissue from the ischemia-reperfusion injury model revealed that MIF-2/D-DT treatment stimulates secretory leukocyte proteinase inhibitor (SLPI) and cyclin D1 expression. MIF-2/D-DT additionally activates of eukaryotic initiation factor (eIF) 2α and activating transcription factor (ATF) 4, two transcription factors involved in the integrated stress response (ISR), which is a cellular stress response activated by hypoxia, nutrient deprivation, and oxygen radicals. MIF-2/D-DT also inhibited apoptosis and induced autophagy in hypoxia-treated mouse proximal tubular (MPT) cells. These results indicate that MIF-2/D-DT is an important factor in tubular cell regeneration and may be of therapeutic utility as a regenerative agent in the clinical setting of ischemic acute kidney injury.
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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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Basile, David P., Daniel R. Martin, and Marc R. Hammerman. "Extracellular matrix-related genes in kidney after ischemic injury: potential role for TGF-β in repair." American Journal of Physiology-Renal Physiology 275, no. 6 (December 1, 1998): F894—F903. http://dx.doi.org/10.1152/ajprenal.1998.275.6.f894.
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The renal expression of transforming growth factor-β1 (TGF-β1) is enhanced following induction of ischemic injury in rat. In cultured renal cells, TGF-β stimulates the synthesis of extracellular matrix. To link TGF-β1 expression with the regulation of extracellular matrix postischemia, we characterized the expression of several genes known to regulate extracellular matrix synthesis at various times during recovery from acute ischemic renal injury in rat. Levels of mRNA for plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloprotease-1 (TIMP-1), α1(IV) collagen, and fibronectin-EIIIA (FN-EIIIA) mRNAs were significantly enhanced in kidneys within 12 h to 3 days after injury and remained elevated at 7–28 days postischemia relative to levels in kidneys of sham-operated controls. PAI-1 mRNA and peptide were localized in regenerating proximal tubules at 3 and 7 days postischemic injury. α1(IV) Collagen and FN-EIIIA mRNAs were expressed primarily in regenerating proximal tubule cells. Immunoreactivity for FN-EIIIA was enhanced in the tubular basement membrane (TBM) of regenerating proximal tubules, and α1(IV) collagen immunoreactivity was detected in thickened tubulointerstitial spaces. In contrast, TIMP-1 immunoreactivity was enhanced in distal nephron structures postischemia. Immunoneutralization of TGF-β in vivo attenuated the increases in FN-EIIIA, α1(IV) collagen, PAI-1, and TIMP-1 mRNAs by 52%, 73%, 43%, and 27%, respectively. These data are consistent with TGF-β expression postischemic injury participating in renal regeneration of extracellular matrix homeostasis in the proximal TBM.
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Bianchini, Marta, Silvestro Micera, and Eugenio Redolfi Riva. "Recent Advances in Polymeric Drug Delivery Systems for Peripheral Nerve Regeneration." Pharmaceutics 15, no. 2 (February 14, 2023): 640. http://dx.doi.org/10.3390/pharmaceutics15020640.
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When a traumatic event causes complete denervation, muscle functional recovery is highly compromised. A possible solution to this issue is the implantation of a biodegradable polymeric tubular scaffold, providing a biomimetic environment to support the nerve regeneration process. However, in the case of consistent peripheral nerve damage, the regeneration capabilities are poor. Hence, a crucial challenge in this field is the development of biodegradable micro- nanostructured polymeric carriers for controlled and sustained release of molecules to enhance nerve regeneration. The aim of these systems is to favor the cellular processes that support nerve regeneration to increase the functional recovery outcome. Drug delivery systems (DDSs) are interesting solutions in the nerve regeneration framework, due to the possibility of specifically targeting the active principle within the site of interest, maximizing its therapeutical efficacy. The scope of this review is to highlight the recent advances regarding the study of biodegradable polymeric DDS for nerve regeneration and to discuss their potential to enhance regenerative performance in those clinical scenarios characterized by severe nerve damage.
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GOBÉ, GLENDA, XIAO-JU ZHANG, DESLEY A. WILLGOSS, ESTELLE SCHOCH, NICOLE A. HOGG, and ZOLTÁN H. ENDRE. "Relationship between Expression of Bcl-2 Genes and Growth Factors in Ischemic Acute Renal Failure in the Rat." Journal of the American Society of Nephrology 11, no. 3 (March 2000): 454–67. http://dx.doi.org/10.1681/asn.v113454.
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Abstract. The promotion of cell survival and regeneration in acute renal failure (ARF) is important for restitution of renal function. This study analyzes the temporal and spatial relationship between expression of pro- and anti-apoptotic members of the Bcl-2 gene family (Bcl-2, Bcl-XL, Bax) and epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and transforming growth factor-β (TGF-β), growth factors that are thought to be reparative in ARF. A rat model of ischemic ARF involving 30 min of bilateral renal artery occlusion followed by reperfusion for 0 to 14 d was used. Apoptosis and mitosis were quantified and qualitative assessment was made of other cellular damage including necrosis and loss of cellular adhesion. Locality and level of expression of the Bcl-2 and growth factor proteins were determined using immunohistochemistry. Apoptosis peaked between 4 and 14 d postischemia in both proximal and distal tubules. Mitosis peaked at 2 d in proximal tubules and 4 to 14 in the distal tubules. A spatio-temporal relationship was observed between anti-apoptotic Bcl-2 gene family members and growth factors after ischemia-reperfusion. In control kidneys, expression of Bcl-2, Bcl-XL was low in epithelium of distal tubules, Bax had low-to-moderate expression in the proximal tubule and had low expression in the distal tubule, EGF and IGF-1 had low-to-moderate expression in the distal tubule, and TGF-β had low expression in the proximal tubule. In contrast, within 24 h of reperfusion, distal tubules showed a marked increase in expression of Bcl-2 and a moderate increase in Bcl-XL and Bax. Proximal tubules showed a marked increase in Bax expression and a moderate increase in Bcl-XL. Twenty-four hours after expression of the Bcl-2 proteins was increased, IGF-1 and EGF protein levels were increased in the distal tubule, similar to the Bcl-2 anti-apoptotic proteins, and were also detected in the adjacent proximal tubules, suggestive of paracrine action in these tubules. TGF-β expression was moderately increased in regenerating proximal tubules, but no relationship was seen with the pattern of expression of the Bcl-2 genes. An explanation of these results is that the distal tubule is adaptively resistant to ischemic injury via promotion of survival by anti-apoptotic Bcl-2 genes, and its survival allows expression of growth factors critical not only to the maintenance and regeneration of its own cell population (autocrine action), but also to the adjacent ischemia-sensitive proximal tubular cells (paracrine action).
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Huang, Jinhui, Enrong Wang, and Hailong Zhang. "Analysis and Research on the Comprehensive Performance of Vehicle Magnetorheological Regenerative Suspension." Vehicles 2, no. 4 (October 22, 2020): 576–88. http://dx.doi.org/10.3390/vehicles2040033.
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Magnetorheological (MR) regenerative suspension system can not only achieve excellent comprehensive suspension performance but also effectively recover and utilize vibration potential energy, which has been a research hotspot in the field of vehicle engineering. In this paper, for the 1/4 vehicle’s MR regenerative suspension system parallel with a tubular permanent magnet linear motor (TPMLM), the dynamic model of the MR semi-active suspension system and the TPMLM finite element model are established separately to form a joint simulation platform. The simulation analysis of the comprehensive suspension performance and regeneration performance under different road excitations is performed. The results show that installing TPMLM does not change the natural resonance frequency of the suspension system, which ensures good driving comfort and handling stability. At the same time, it has considerable regeneration power. This research can provide a reference for the stability analysis and popularization of the vehicle’s MR regenerative suspension system.
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Smeets, Bart, Peter Boor, Henry Dijkman, Shagun V. Sharma, Peggy Jirak, Fieke Mooren, Katja Berger, et al. "Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration." Journal of Pathology 229, no. 5 (March 13, 2013): 645–59. http://dx.doi.org/10.1002/path.4125.
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Lee, Yoon, Yeoung-Hyun Park, Dong-Seol Lee, You-Mi Seo, Ji-Hyun Lee, Joo-Hwang Park, Han-Wool Choung, So-Hyun Park, Won Shon, and Joo-Cheol Park. "Tubular Dentin Regeneration Using a CPNE7-Derived Functional Peptide." Materials 13, no. 20 (October 16, 2020): 4618. http://dx.doi.org/10.3390/ma13204618.
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We aim to examine the effects of a newly developed peptide derived from CPNE7 (Cpne7-DP) in tertiary dentin formation and peritubular space occlusion, and comprehensively evaluate its potential as a bioactive therapeutic agent. Human dental pulp cells (HDPCs) and a mouse pre-odontoblast cell line, MDPC-23, were chosen for in vitro studies to characterize lineage-specific cell responses after Cpne7-DP treatment. Whether Cpne7-DP reproduces the dentin regenerative potential of CPNE7 was tested using a beagle dog model by generating dentinal defects of various degrees in vivo. Peritubular space occlusion was further examined by scanning electron microscopy and microleakage test, while overall mineralization capacity of Cpne7-DP was tested ex vivo. CPNE7 promotes tubular dentin formation under both shallow and deep dentinal defects, and the functional peptide Cpne7-DP induces odontoblast-like differentiation in vitro, mineralization ex vivo, and tubular dentin formation in in vivo beagle dog dentin exposure and pulp exposure models. Moreover, Cpne7-DP leads to peritubular space occlusion and maintains stability under different conditions. We show that CPNE7 and its derivative functional peptide Cpne7-DP promotes dentin regeneration in dentinal defects of various degrees and that the regenerated hard tissue demonstrates the characteristics of true dentin. Limitations of the current dental materials including post-operative hypersensitivity make biological repair of dentin a field of growing interest. Here, we suggest that the dual functions of Cpne7-DP in tubular dentin formation and peritubular space occlusion are promising for the treatment of dentinal loss and sensitivity.
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VERCAUTEREN, SVEN R., DIRK K. YSEBAERT, KATHLEEN E. DE GREEF, ERIK J. EYSKENS, and MARC E. DE BROE. "Chronic Reduction in Renal Mass in the Rat Attenuates Ischemia/Reperfusion Injury and Does Not Impair Tubular Regeneration." Journal of the American Society of Nephrology 10, no. 12 (December 1999): 2551–61. http://dx.doi.org/10.1681/asn.v10122551.
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Abstract. It is not known whether a kidney with chronic structural and functional changes is more vulnerable to an acute renal insult, and whether its regeneration capacity after injury is altered. To study this question, Lewis rats were submitted 10 wk after 5/6 nephrectomy to an ischemic insult of 60 min (remnant kidney [RK] group). Functional and morphologic data of the RK group were compared with data obtained in 10-wk uninephrectomized (1K) and normal (2K) Lewis rats with unilateral and bilateral renal ischemia, respectively. The acute postischemic decrease in creatinine clearance was smallest in the RK group, followed by the 2K and 1K groups, respectively. At days 1 and 3, fewer proximal tubules in the outer stripe of the outer medulla of the RK and 2K groups had undergone acute tubular necrosis compared with the 1K group. The mean percentage of tubules with signs of regeneration was maximal at day 3 in the three experimental groups. At day 10, regeneration was almost complete in the three groups. The number of leukocytes (OX1+cells) present in the RK before ischemia did not increase after ischemia/reperfusion injury (377 ± 146 cells/mm2at day 0) in contrast to the 1K and 2K groups. In the latter groups, the number of leukocytes had increased gradually, reaching a maximum at day 15 (1K: 960 ± 308 cells/mm2) and day 10 (2K: 668 ± 164 cells/mm2), respectively. In conclusion, this study has shown that an RK exhibiting chronic morphologic changes of interstitial fibrosis and tubular atrophy is protected against ischemia/reperfusion injury, and that its regeneration capacity is preserved. The reperfusion injury is not followed by further accumulation of leukocytes, which were already present in the RK before ischemia.
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Andrianova, Nadezda V., Marina I. Buyan, Ljubava D. Zorova, Irina B. Pevzner, Vasily A. Popkov, Valentina A. Babenko, Denis N. Silachev, Egor Y. Plotnikov, and Dmitry B. Zorov. "Kidney Cells Regeneration: Dedifferentiation of Tubular Epithelium, Resident Stem Cells and Possible Niches for Renal Progenitors." International Journal of Molecular Sciences 20, no. 24 (December 15, 2019): 6326. http://dx.doi.org/10.3390/ijms20246326.
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A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a “progenitor phenotype” during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues.
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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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Prasetyo, R. V., I. Surono, N. A. Soemyarso, T. Djojodimedjo, S. Rauf, M. S. Noer, and S. M. Sudarmo. "Lactobacillus plantarum IS-10506 promotes renal tubular regeneration in pyelonephritic rats." Beneficial Microbes 11, no. 1 (February 19, 2020): 59–66. http://dx.doi.org/10.3920/bm2019.0036.
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Lactobacillus plantarum IS-10506 is a novel probiotic isolated from Indonesian traditional fermented buffalo milk dadih. Probiotics are clinically proven to be effective in accelerating recovery after urinary tract infection (UTI) and in decreasing recurrent UTI in children with or without structural disorders of the urinary tract. This study aimed to investigate the role of the probiotic L. plantarum IS-10506 in activating and regenerating renal epithelial stem cells in pyelonephritic rats. Fifty-five 20-weeks-old male Sprague-Dawley rats were randomised into control, lipopolysaccharide (LPS) and treatment (LPS and probiotic) groups. Pyelonephritis was induced with Escherichia coli ATCC 25922 LPS administered via a urethral catheter on the first experimental day to the LPS and treatment groups. Microencapsulated L. plantarum IS-10506 was orally administered once daily for up to 14 days to the treatment group. On days 3, 5, 7, 10 and 14, five rats per group were sacrificed and their kidneys were immunohistochemically analysed for production of interleukin (IL)-10, lipocalin-2 and Ki-67 in the renal tubular cells. IL-10 production was upregulated starting from day 3 through day 14 in the treatment group (P<0.05) compared with that in the control and LPS groups. Moreover, treatment with the probiotic led to increased activation of renal tubular stem cell, as indicated by a higher lipocalin-2 production, and further proliferation of renal tubular stem cells was documented by a higher Ki-67 production. Taken together, these results indicate that the anti-inflammatory probiotic L. plantarum IS-10506 improves renal injury in pyelonephritic rats by activating endogenous renal tubular stem cells to proliferate into mature renal tubular epithelial cells.
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Urbschat, Anja, Anne-Kathrin Thiemens, Christina Mertens, Claudia Rehwald, Julia K. Meier, Patrick C. Baer, and Michaela Jung. "Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells." International Journal of Molecular Sciences 21, no. 6 (March 16, 2020): 2038. http://dx.doi.org/10.3390/ijms21062038.
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Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load for its pro-regenerative function. Primary mouse tubular epithelial cells were isolated from kidney tissue of wildtype mice and incubated with 5 µM Cisplatin for 24 h to induce injury. Bone marrow-derived macrophages of wildtype and Lcn-2−/− mice were isolated and polarized with IL-10 towards an anti-inflammatory, iron-release phenotype. Their supernatants as well as recombinant iron-loaded holo-Lcn-2 was used for stimulation of Cisplatin-injured tubular epithelial cells. Incubation of tubular epithelial cells with wildtype supernatants resulted in less damage and induced cellular proliferation, whereas in absence of Lcn-2 no protective effect was observed. Epithelial integrity as well as cellular proliferation showed a clear protection upon rescue experiments applying holo-Lcn-2. Notably, we detected a positive correlation between total iron amounts in tubular epithelial cells and cellular proliferation, which, in turn, reinforced the assumed link between availability of Lcn-2-bound iron and recovery. We hypothesize that macrophage-released Lcn-2-bound iron is provided to tubular epithelial cells during toxic cell damage, whereby injury is limited and recovery is favored.
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De Filippo, Roger, Laura Perin, Stefano Giuliani, Akito Maeshima, Daniel Jin, Sargis Sedrakyan, and Anthony Atala. "Renal tubular regeneration from human Amniotic Fluid Stem Cells." Journal of the American College of Surgeons 201, no. 3 (September 2005): S47. http://dx.doi.org/10.1016/j.jamcollsurg.2005.06.100.
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Vansthertem, D., N. Caron, A. E. Decleves, S. Cludts, A. Gossiaux, D. Nonclercq, B. Flamion, A. Legrand, and G. Toubeau. "Label-retaining cells and tubular regeneration in postischaemic kidney." Nephrology Dialysis Transplantation 23, no. 12 (July 16, 2008): 3786–97. http://dx.doi.org/10.1093/ndt/gfn412.
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Romagnani, Paola. "Of mice and men: the riddle of tubular regeneration." Journal of Pathology 229, no. 5 (February 11, 2013): 641–44. http://dx.doi.org/10.1002/path.4162.
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Jeong, Hun-Jin, Hyoryung Nam, Jinah Jang, and Seung-Jae Lee. "3D Bioprinting Strategies for the Regeneration of Functional Tubular Tissues and Organs." Bioengineering 7, no. 2 (March 31, 2020): 32. http://dx.doi.org/10.3390/bioengineering7020032.
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It is difficult to fabricate tubular-shaped tissues and organs (e.g., trachea, blood vessel, and esophagus tissue) with traditional biofabrication techniques (e.g., electrospinning, cell-sheet engineering, and mold-casting) because these have complicated multiple processes. In addition, the tubular-shaped tissues and organs have their own design with target-specific mechanical and biological properties. Therefore, the customized geometrical and physiological environment is required as one of the most critical factors for functional tissue regeneration. 3D bioprinting technology has been receiving attention for the fabrication of patient-tailored and complex-shaped free-form architecture with high reproducibility and versatility. Printable biocomposite inks that can facilitate to build tissue constructs with polymeric frameworks and biochemical microenvironmental cues are also being actively developed for the reconstruction of functional tissue. In this review, we delineated the state-of-the-art of 3D bioprinting techniques specifically for tubular tissue and organ regeneration. In addition, this review described biocomposite inks, such as natural and synthetic polymers. Several described engineering approaches using 3D bioprinting techniques and biocomposite inks may offer beneficial characteristics for the physiological mimicry of human tubular tissues and organs.
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Morrow, Carla M. K., Victor E. Valli, Petra A. Volmer, and Paul A. Eubig. "Canine Renal Pathology Associated with Grape or Raisin Ingestion: 10 Cases." Journal of Veterinary Diagnostic Investigation 17, no. 3 (May 2005): 223–31. http://dx.doi.org/10.1177/104063870501700302.
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Ten dogs suffered acute renal failure after ingesting ≥3 g/kg (dry matter) of grapes or raisins. All dogs had degeneration or necrosis (or both) of proximal renal tubules with basement membranes remaining intact, and epithelial regeneration was observed in 5 out of 10 cases. Mineralized tubular debris or granular to proteinaceous casts (or both) were present in all cases. A golden-brown, globular, intracellular pigment of varying amounts and sizes was observed in 6 out of 10 cases with variable reaction with Prussian blue. Multifocal fibrinous arteritis of the large colon was seen in 2 out of 5 cases with globulin insudation of vessel wall demonstrated by immunohistochemical staining for immunoglobulin (Ig)G and IgM. Mineral analysis on frozen renal tissue from 2 out of 2 cases revealed mildly elevated Ca:P ratio in both. Clinically significant observations were preservation of the integrity of basement membranes after grape-induced tubular injury and presence of early epithelial regeneration. Thus, recovery may be possible if anuria is aggressively managed. With respect to potential pathophysiologic mechanisms, further research into the roles of calcium homeostasis, vascular reactivity, and the significance of the golden-brown pigment is indicated.
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Cornec, Jean-Pierre. "Étude ultrastructurale des bourgeons de régénération mis en place après amputation de la ventouse postérieure chez l'hirudinée rhynchobdelle adulte Helobdella stagnalis." Canadian Journal of Zoology 68, no. 2 (February 1, 1990): 303–12. http://dx.doi.org/10.1139/z90-045.
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Tissue behaviour in the rhynchobdellid hirudinean, Helobdella stagnalis, was studied at the ultrastructural level between 8 and 18 days after amputation of the posterior sucker. Ultrastructural transformations of the regenerative buds progress in a sequential mode. They are successively characterized by nerve fiber regeneration, differentiation of the adhesive sole, and muscular and conjonctive tissues reconstitution with cells provided by the stump. Adhesive sole differentiation involves, first, the basal cells, which occurs without previous dedifferentiation, then the sensory receptors and, lastly, the glandular cells. Some basal epidermal cells are at the origin of the mucus glandular cells. The piriform and tubular phenotypes must be considered as successive maturation stages of the same clone. The conjunctive extracellular matrix probably plays a primordial role in the differentiation of the specific tubular glands of the adhesive sole.
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Chang, B., C. Ma, J. Feng, K. K. H. Svoboda, and X. Liu. "Dental Pulp Stem Cell Polarization: Effects of Biophysical Factors." Journal of Dental Research 100, no. 10 (July 30, 2021): 1153–60. http://dx.doi.org/10.1177/00220345211028850.
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Dental pulp stem cells (DPSCs) have the potential to polarize, differentiate, and form tubular dentin under certain conditions. However, the factors that initiate and regulate DPSC polarization and its underlying mechanism remain unclear. Identification of the factors that control DPSC polarization is a prerequisite for tubular dentin regeneration. We recently developed a unique bioinspired 3-dimensional platform that is capable of deciphering the factors that initiate and modulate cell polarization. The bioinspired platform has a simple background and confines a single cell on each microisland of the platform; therefore, it is an effective tool to study DPSC polarization at the single-cell level. In this work, we explored the effects of biophysical factors (surface topography, microisland area, geometry, tubular size, and gravity) on single DPSC polarization. Our results demonstrated that nanofibrous architecture, microisland area, tubular size, and gravity participated in regulating DPSC polarization by influencing the formation of the DPSC process and relocation of the Golgi apparatus. Among these factors, nanofibrous architecture, tubular size, and appropriate microisland area were indispensable for initiating DPSC polarization, whereas gravity served as an auxiliary factor to the process of DPSC polarization. Meanwhile, microisland geometry had a limited effect on DPSC polarization. Collectively, this work provides information on DPSC polarization and paves the way for the development of new biomaterials for tubular dentin regeneration.
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Zhuang, Shougang, Yan Yan, Rebecca A. Daubert, and Rick G. Schnellmann. "Epiregulin promotes proliferation and migration of renal proximal tubular cells." American Journal of Physiology-Renal Physiology 293, no. 1 (July 2007): F219—F226. http://dx.doi.org/10.1152/ajprenal.00082.2007.
Full textAbstract:
Epiregulin is an epidermal growth factor (EGF) member that activates ErBB1 and ErBB4 homodimers and all possible heterodimeric ErbB complexes. Because its role in renal cell regeneration has not been investigated, we assessed the effect of exogenous epiregulin on regeneration of renal proximal tubular cells (RPTC) in primary culture. Epiregulin (10 ng/ml) was equivalent to EGF (10 ng/ml) in enhancing RPTC proliferation and migration. Epiregulin induced activation of the EGF receptor (EGFR), Akt, a downstream kinase of phosphoinositide 3-kinase (PI3K), and extracellular signaling-regulated kinase 1/2 (ERK1/2). Treatment with AG1478, a specific EGFR inhibitor, blocked phosphorylation of EGFR, Akt, ERK1/2, proliferation, and migration. Furthermore, inactivation of PI3K with LY-294002 blocked epiregulin-induced RPTC proliferation and, to a lesser extent, migration. However, blockade of ERK1/2 had no such effects. We suggest that epiregulin is a potent mitogen for renal epithelial cells and may contribute to renal regeneration through activation of EGFR and PI3/Akt pathways.
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Adepu, Saritha, Colin W. K. Rosman, Wendy Dam, Marcory C. R. F. van Dijk, Gerjan Navis, Harry van Goor, Stephan J. L. Bakker, and Jacob van den Born. "Incipient renal transplant dysfunction associates with tubular syndecan-1 expression and shedding." American Journal of Physiology-Renal Physiology 309, no. 2 (July 15, 2015): F137—F145. http://dx.doi.org/10.1152/ajprenal.00127.2015.
Full textAbstract:
Syndecan-1 is a transmembrane heparan sulfate proteoglycan involved in regenerative growth and cellular adhesion. We hypothesized that the induction of tubular syndecan-1 is a repair response to incipient renal damage in apparently stable, uncomplicated renal transplant recipients. We quantified tubular syndecan-1 in unselected renal protocol biopsies taken 1 yr after transplantation. Spearman rank correlation analysis revealed an inverse correlation between tubular syndecan-1 expression and creatinine clearance at the time of biopsy ( r = −0.483, P < 0.03). In a larger panel of protocol and indication biopsies from renal transplant recipients, tubular syndecan-1 correlated with tubular proliferation marker Ki67 ( r = 0.518, P < 0.0001). In a rat renal transplantation model, 2 mo after transplantation, mRNA expression of syndecan-1 and its major sheddase, A disintegrin and metalloproteinase-17, were upregulated (both P < 0.03). Since shed syndecan-1 might end up in the circulation, in a stable cross-sectional human renal transplant population ( n = 510), we measured plasma syndecan-1. By multivariate regression analysis, we showed robust independent associations of plasma syndecan-1 with renal (plasma creatinine and plasma urea) and endothelial function parameters (plasma VEGF-A, all P < 0.01). By various approaches, we were not able to localize syndecan-1 in vessel wall or endothelial cells, which makes shedding of syndecan-1 from the endothelial glycocalyx unlikely. Our data suggest that early damage in transplanted kidneys induces repair mechanisms within the graft, namely, tubular syndecan-1 expression for tubular regeneration and VEGF production for endothelial repair. Elevated plasma syndecan-1 levels in renal transplantation patients might be interpreted as repair/survival factor related to loss of tubular and endothelial function in transplanted kidneys.
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Miller, S. B., D. R. Martin, J. Kissane, and M. R. Hammerman. "Hepatocyte growth factor accelerates recovery from acute ischemic renal injury in rats." American Journal of Physiology-Renal Physiology 266, no. 1 (January 1, 1994): F129—F134. http://dx.doi.org/10.1152/ajprenal.1994.266.1.f129.
Full textAbstract:
Effects of hepatocyte growth factor (HGF) administration were examined in a model of acute ischemic renal injury induced by bilateral renal artery occlusion in rats. Compared with rats administered vehicle, rats administered 20 micrograms HGF subcutaneously 30 min postischemia had significantly lower serum creatinine and blood urea nitrogen levels over the course of 7 days postocclusion, enhanced insulin clearances measured on day 2 postocclusion, reduced mortality, and much less injury evident by examination of kidney histologies 7 days postinjury. The tubular regeneration that occurred postischemic injury was reflected by increased incorporation of 5-bromo-2'-deoxyuridine (BrdU) in cortical tubular epithelium compared with incorporation in kidneys from noninjured rats. HGF enhanced BrdU incorporation compared with vehicle, indicating enhanced mitogenesis. The weight loss that occurs postischemic injury was not ameliorated by the dose of HGF we employed. We conclude that administration of HGF postischemic injury to rats stimulates the recovery of normal kidney function and the regeneration of proximal tubular epithelium.
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Machado, Ana Lourdes da Silva, Adriana Aigotti Haberbeck Brandão, Cláudia Maria de Oliveira Monteiro da Silva, and Rosilene Fernandes da Rocha. "Influence of tetracycline in the hepatic and renal development of rat's offspring." Brazilian Archives of Biology and Technology 46, no. 1 (January 2003): 47–52. http://dx.doi.org/10.1590/s1516-89132003000100008.
Full textAbstract:
This study aimed on evaluating the possible effects of tetracycline administered to rats on the tenth day of pregnancy, on kidney and liver development of their offspring. The liver showed vacuolization, necrosis, inflammation and sinusoidal dilatations, more evident in the newborn. Mitosis, early increase of Kupffer cells population and hipertrophy of hepatocytes with greater synthesis of glycogen were present on the tenth and twentieth days of life. The kidney showed slight tubular vacuolizations and necrosis, more proeminent in the newborn, as well as signs of tubular regeneration on the tenth and twentieth days. These results suggested that the organs studied went through several transitory morphological changes during development but presented signs of regeneration along the first days of life.
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Vesely, David L. "Natriuretic peptides and acute renal failure." American Journal of Physiology-Renal Physiology 285, no. 2 (August 2003): F167—F177. http://dx.doi.org/10.1152/ajprenal.00259.2002.
Full textAbstract:
Atrial natriuretic peptides (ANPs) are a family of peptide hormones, e.g., ANP, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide synthesized by the ANP gene. Brain natriuretic peptide (BNP) and C-type natriuretic peptide are also members of this family but are synthesized by separate genes. Within the kidney, the ANP prohormone's posttranslational processing is different from that of other tissues, resulting in an additional four amino acids added to the NH2terminus of ANP (e.g., urodilatin). Each of these natriuretic and diuretic peptides increases within the circulation with acute renal failure (ARF). Renal transplantation but not hemodialysis returns their circulating concentrations to those of healthy individuals. BNP and adrenomedullin, a 52-amino acid natriuretic peptide, have beneficial effects on glomerular hypertrophy and glomerular injury but do not improve tubular injury (i.e., acute tubular necrosis). Vessel dilator ameliorates acute tubular necrosis with regeneration of the brush borders of proximal tubules. Vessel dilator decreases mortality in ARF from 88 to 14% at day 6 of ARF, even when given 2 days after renal failure has been established.
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Bianchi, Eleonora, Angela Faccendini, Elena Del Favero, Caterina Ricci, Laura Caliogna, Barbara Vigani, Francesco Claudio Pavesi, et al. "Topographical and Compositional Gradient Tubular Scaffold for Bone to Tendon Interface Regeneration." Pharmaceutics 14, no. 10 (October 10, 2022): 2153. http://dx.doi.org/10.3390/pharmaceutics14102153.
Full textAbstract:
The enthesis is an extremely specific region, localized at the tendon–bone interface (TBI) and made of a hybrid connection of fibrocartilage with minerals. The direct type of enthesis tissue is commonly subjected to full laceration, due to the stiffness gradient between the soft tissues and hard bone, and this often reoccurs after surgical reconstruction. For this purpose, the present work aimed to design and develop a tubular scaffold based on pullulan (PU) and chitosan (CH) and intended to enhance enthesis repair. The scaffold was designed with a topographical gradient of nanofibers, from random to aligned, and hydroxyapatite (HAP) nanoparticles along the tubular length. In particular, one part of the tubular scaffold was characterized by a structure similar to bone hard tissue, with a random mineralized fiber arrangement; while the other part was characterized by aligned fibers, without HAP doping. The tubular shape of the scaffold was also designed to be extemporarily loaded with chondroitin sulfate (CS), a glycosaminoglycan effective in wound healing, before the surgery. Micro CT analysis revealed that the scaffold was characterized by a continuous gradient, without interruptions from one end to the other. The gradient of the fiber arrangement was observed using SEM analysis, and it was still possible to observe the gradient when the scaffold had been hydrated for 6 days. In vitro studies demonstrated that human adipose stem cells (hASC) were able to grow and differentiate onto the scaffold, expressing the typical ECM production for tendon in the aligned zone, or bone tissue in the random mineralized part. CS resulted in a synergistic effect, favoring cell adhesion/proliferation on the scaffold surface. These results suggest that this tubular scaffold loaded with CS could be a powerful tool to support enthesis repair upon surgery.