Journal articles: 'Tubulointerstitial fibrosis'

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O'Donnell, Michael P. "Renal tubulointerstitial fibrosis." Postgraduate Medicine 108, no. 1 (July 2000): 159–72. http://dx.doi.org/10.3810/pgm.2000.07.1155.

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Zeisberg, Michael, and Eric G. Neilson. "Mechanisms of Tubulointerstitial Fibrosis." Journal of the American Society of Nephrology 21, no. 11 (September 23, 2010): 1819–34. http://dx.doi.org/10.1681/asn.2010080793.

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Kuncio, Gerald S., Eric G. Neilson, and Thomas Haverty. "Mechanisms of tubulointerstitial fibrosis." Kidney International 39, no. 3 (March 1991): 550–56. http://dx.doi.org/10.1038/ki.1991.63.

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Iwano, Masayuki, and Eric G. Neilson. "Mechanisms of tubulointerstitial fibrosis." Current Opinion in Nephrology and Hypertension 13, no. 3 (May 2004): 279–84. http://dx.doi.org/10.1097/00041552-200405000-00003.

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VIELHAUER, VOLKER, HANS-JOACHIM ANDERS, MATTHIAS MACK, JOSEF CIHAK, FRANK STRUTZ, MANFRED STANGASSINGER, BRUNO LUCKOW, HERMANN-JOSEF GRÖNE, and DETLEF SCHLÖNDORFF. "Obstructive Nephropathy in the Mouse: Progressive Fibrosis Correlates with Tubulointerstitial Chemokine Expression and Accumulation of CC Chemokine Receptor 2- and 5-Positive Leukocytes." Journal of the American Society of Nephrology 12, no. 6 (June 2001): 1173–87. http://dx.doi.org/10.1681/asn.v1261173.

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Abstract. The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. Byin situhybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor—mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.

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Thomas, S. E., S. Anderson, K. L. Gordon, T. T. Oyama, S. J. Shankland, and R. J. Johnson. "Tubulointerstitial disease in aging: evidence for underlying peritubular capillary damage, a potential role for renal ischemia." Journal of the American Society of Nephrology 9, no. 2 (February 1998): 231–42. http://dx.doi.org/10.1681/asn.v92231.

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Aging is associated with a progressive decline in renal function and the development of glomerulosclerosis and interstitial fibrosis. Although many studies have addressed the cellular mechanisms of age-related glomerulosclerosis, less is known about the tubulointerstitial fibrosis. In this study, aging (24 mo) rats develop tubulointerstitial fibrosis characterized by tubular injury and focal tubular cell proliferation, myofibroblast activation, macrophage infiltration with increased immunostaining for the adhesive proteins osteopontin and intercellular adhesion molecule-1, and collagen IV deposition. Aging rats demonstrated immunostaining for endothelial nitric oxide synthase (eNOSIII) in renal tubular epithelial cells and infiltrating mononuclear cells in areas of tubulointerstitial injury, with a relative loss of staining of the peritubular capillaries compared with young rats. The aging rats also displayed focal loss of peritubular capillaries (as noted by focally decreased RECA-1 and OX-2 staining) in areas of tubulointerstitial injury. The areas of fibrosis and hypocellularity were associated with increased apoptosis of tubular and interstitial cells compared with young (3 mo) rats (25.4 +/- 5.3 versus 3.5 +/- 2.5 TUNEL-positive cells/0.25 mm2 in old versus young rats, P = 0.0001). It is concluded that tubulointerstitial fibrosis in aging is an active process associated with interstitial inflammation and fibroblast activation. The progressive loss of cells in areas of fibrosis may be due to accelerated apoptosis. Furthermore, the tubulointerstitial injury may be the consequence of ischemia secondary to peritubular capillary injury and altered eNOS expression.

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Ito, Hideyuki, Xiaoxiang Yan, Nanae Nagata, Kosuke Aritake, Yoshinori Katsumata, Tomohiro Matsuhashi, Masataka Nakamura, et al. "PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis." Journal of the American Society of Nephrology 23, no. 11 (September 20, 2012): 1797–809. http://dx.doi.org/10.1681/asn.2012020126.

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Boor, Peter, Andrzej Konieczny, Luigi Villa, Anna-Lisa Schult, Eva Bücher, Song Rong, Uta Kunter, et al. "Complement C5 Mediates Experimental Tubulointerstitial Fibrosis." Journal of the American Society of Nephrology 18, no. 5 (March 27, 2007): 1508–15. http://dx.doi.org/10.1681/asn.2006121343.

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Sakamoto, Izumi, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Akiho Sawai, Akio Tanaka, Shoichi Maruyama, Yoshifumi Takei, Yukio Yuzawa, and Seiichi Matsuo. "Lymphatic vessels develop during tubulointerstitial fibrosis." Kidney International 75, no. 8 (April 2009): 828–38. http://dx.doi.org/10.1038/ki.2008.661.

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SATOH, MINORU, NAOKI KASHIHARA, YASUSHI YAMASAKI, KEISUKE MARUYAMA, KAZUNORI OKAMOTO, YOUHEI MAESHIMA, HITOSHI SUGIYAMA, TAKESHI SUGAYA, KAZUO MURAKAMI, and HIROFUMI MAKINO. "Renal Interstitial Fibrosis Is Reduced in Angiotensin II Type 1a Receptor-Deficient Mice." Journal of the American Society of Nephrology 12, no. 2 (February 2001): 317–25. http://dx.doi.org/10.1681/asn.v122317.

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Abstract. Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin-angiotensin system. This study established a UUO model in angiotensin type 1a receptor (AT1a) deficient (mutant) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney (OBK). The relative volume of the tubulointerstitium was measured by an image analyzer; deposition of collagen types III and IV and monocyte/macrophage infiltration were histologically examined using specific antibodies. Also determined were the mRNA levels of transforming growth factor-β by Northern blot analysis. Nuclear factor-κB activity was assessed by gel shift assay. UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium, together with increased deposition of collagen types III and IV and number of infiltrated monocytes/macrophages in the interstitium, relative to sham-operated mice. In comparison, these changes were significantly lower in mutant mice with UUO. The mRNA level of transforming growth factor-β was significantly higher in the OBK of wild mice with UUO compared with sham-operated mice. In contrast, the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice. Finally, UUO resulted in activation of nuclear factor-κB in wild mice but was inhibited in the OBK of mutant mice. The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO.

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Hewitson, Tim D. "Renal tubulointerstitial fibrosis: common but never simple." American Journal of Physiology-Renal Physiology 296, no. 6 (June 2009): F1239—F1244. http://dx.doi.org/10.1152/ajprenal.90521.2008.

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Regardless of etiology, all patients with chronic renal disease show a progressive decline in renal function with time. Fibrosis, so-called scarring, is a key cause of this pathophysiology. Fibrosis involves an excess accumulation of extracellular matrix (primarily composed of collagen) and usually results in loss of function when normal tissue is replaced with scar tissue. While recent major advances have led to a much better understanding of this process, many problems remain. We for instance know little about why some wounds heal and others scar and little about how many putative antifibrotic agents work. This review discusses recent advances in our understanding of the mechanisms of tubulointerstitial fibrosis, focusing on the regulation and role of the myofibroblast in this process, the role of recently recognized endogenous antifibrotic factors, controversy surrounding the effects of metalloproteinases, and the opportunities presented by new treatment strategies that abrogate and may even reverse fibrosis.

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Wu, Jinhao, Chao Huang, Gang Kan, Hanyu Xiao, Xiaoping Zhang, and Jun Yang. "Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy." Current Topics in Nutraceutical Research 19, no. 4 (March 17, 2021): 508–13. http://dx.doi.org/10.37290/ctnr2641-452x.19:508-513.

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Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.

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Gewin, Leslie, and Roy Zent. "How Does TGF-β Mediate Tubulointerstitial Fibrosis?" Seminars in Nephrology 32, no. 3 (May 2012): 228–35. http://dx.doi.org/10.1016/j.semnephrol.2012.04.001.

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Li, Dixin, Hongbing Zeng, and Chunyang Ji. "Effect of pirfenidone on renal tubulointerstitial fibrosis." Frontiers of Medicine in China 3, no. 3 (July 10, 2009): 316–22. http://dx.doi.org/10.1007/s11684-009-0045-2.

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Johnson, Richard J., Christian Hugo, Leah Haseley, Raimund Pichler, James Bassuk, Susan Thomas, Shinichi Suga, William G. Couser, and Stuart J. Shankland. "Mechanisms of progressive glomerulosclerosis and tubulointerstitial fibrosis." Clinical and Experimental Nephrology 2, no. 4 (December 1998): 307–12. http://dx.doi.org/10.1007/bf02480459.

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Kümpers, Philipp, Faikah Gueler, Song Rong, Michael Mengel, Irini Tossidou, Imke Peters, Hermann Haller, and Mario Schiffer. "Leptin is a coactivator of TGF-β in unilateral ureteral obstructive kidney disease." American Journal of Physiology-Renal Physiology 293, no. 4 (October 2007): F1355—F1362. http://dx.doi.org/10.1152/ajprenal.00003.2007.

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Progressive tubulointerstitial fibrosis is the common end point leading to end-stage renal disease in experimental and clinical settings. Since the peptide hormone leptin is involved not only in the regulation of obesity but also in the regulation of inflammation and fibrosis, we tested the hypothesis whether leptin deficiency has an impact on tubulointerstitial fibrosis in mice. Leptin-deficient ( ob/ ob) and leptin receptor-deficient mice ( db/ db) were exposed to 14 days of unilateral ureteral obstruction (UUO). The degree of fibrosis and inflammation was compared with that in sham-operated mice by performing immunohistochemistry, quantitative PCR, and Western blotting. We found that tubulointerstitial fibrosis was significantly reduced in the obstructed kidneys of ob/ ob compared with db/ db mice or control mice. Detailed analysis of infiltrating inflammatory cells by immunohistochemistry revealed a significant reduction of CD4+ cells at 14 days after UUO in both ob/ ob and db/ db mice. In contrast, we could not detect significant differences in CD8+ cells and macrophage content. Transforming growth factor (TGF)-β mRNA levels, TGF-β-induced Smad-2/3 activation, and the upregulation of downstream target genes were significantly reduced in ob/ ob mice. In addition, we demonstrated that leptin could enhance TGF-β signaling in normal rat kidney fibroblasts in vitro. We conclude that leptin can serve as a cofactor of TGF-β activation and thus plays an important role in renal tubulointerstitial fibrosis. Therefore, selective blockade of the leptin axis might provide a therapeutic possibility to prevent or delay fibrotic kidney disease.

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Wei, Jinying, Xinna Deng, Yang Li, Runmei Li, Zhaohua Yang, Xiuyuan Li, Shan Song, Yonghong Shi, Huijun Duan, and Haijiang Wu. "PP2 Ameliorates Renal Fibrosis by Regulating the NF-κB/COX-2 and PPARγ/UCP2 Pathway in Diabetic Mice." Oxidative Medicine and Cellular Longevity 2021 (September 17, 2021): 1–24. http://dx.doi.org/10.1155/2021/7394344.

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Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN). We aimed to evaluate the effects of PP2 on renal fibrosis of DN. GSE33744 and GSE86300 were downloaded from the GEO database. Firstly, 839 DEGs were identified between nondiabetic and diabetic mice renal glomerular samples. COX-2 was selected to assess the effects of PP2 on renal glomerulosclerosis. In db/db mice, PP2 decreased the expression of COX-2, phosphorylated p65, and fibrotic proteins, accompanied with attenuated renal glomerulosclerosis. In cultured glomerular mesangial cells, high glucose- (HG-) induced p65 phosphorylation and COX-2 expression were attenuated by PP2 or NF-κB inhibitor PDTC. PP2, PDTC, or COX-2 inhibitor NS-398 ameliorated abnormal proliferation and expression of fibrotic proteins induced by HG. Secondly, 238 DEGs were identified between nondiabetic and diabetic mice renal cortex samples. UCP2 was selected to assess the effects of PP2 on renal tubulointerstitial fibrosis. In db/db mice, PP2 decreased the expression of PPARγ and UCP2, accompanied with attenuated renal tubulointerstitial fibrosis and EMT. In cultured proximal tubular cells, HG-induced PPARγ and UCP2 expression was inhibited by PP2 or PPARγ antagonist GW9662. PP2, GW9662, or UCP2 shRNA ameliorated HG-induced EMT. These results indicated that PP2 ameliorated renal fibrosis in diabetic mice.

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Hruska, Keith A., Guangjie Guo, Magdalena Wozniak, Daniel Martin, Steven Miller, Helen Liapis, Kenneth Loveday, Saulo Klahr, T. Kuber Sampath, and Jeremiah Morrissey. "Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction." American Journal of Physiology-Renal Physiology 279, no. 1 (July 1, 2000): F130—F143. http://dx.doi.org/10.1152/ajprenal.2000.279.1.f130.

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Unilateral ureteral obstruction (UUO) is a model of renal injury characterized by progressive tubulointerstitial fibrosis and renal damage, while relatively sparing the glomerulus and not producing hypertension or abnormalities in lipid metabolism. Tubulointerstitial fibrosis is a major component of several kidney diseases associated with the progression to end-stage renal failure. Here we report that when a critical renal developmental morphogen, osteogenic protein-1 (OP-1; 100 or 300 μg/kg body wt), is administered at the time of UUO and every other day thereafter, interstitial inflammation and fibrogenesis are prevented, leading to preservation of renal function during the first 5 days after obstruction. Compared with angiotensin-converting enzyme inhibition with enalapril treatment, OP-1 was more effective in preventing tubulointerstitial fibrosis and in preserving renal function. The mechanism of OP-1- induced renal protection was associated with prevention of tubular atrophy, an effect not shared with enalapril, and was related to preservation of tubular epithelial integrity. OP-1 blocked the stimulation of epithelial cell apoptosis produced by UUO, which promoted maintenance of tubular epithelial integrity. OP-1 preserved renal blood flow (RBF) during UUO, but enalapril also stimulated RBF. Thus OP-1 treatment inhibited tubular epithelial disruption stimulated by the renal injury of UUO, preventing tubular atrophy and diminishing the activation of tubulointerstitial inflammation and fibrosis and preserving renal function.

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Nasu, Kahori, Takahisa Kawakami, Akinari Shinohara, Takeharu Sakamoto, and Masaomi Nangaku. "Munc18-1-interacting protein 3 mitigates renal fibrosis through protection of tubular epithelial cells from apoptosis." Nephrology Dialysis Transplantation 35, no. 4 (September 8, 2019): 576–86. http://dx.doi.org/10.1093/ndt/gfz177.

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Abstract Background Tubulointerstitial fibrosis is a hallmark of chronic kidney disease (CKD), and is initiated by tubular epithelial cell (TEC) injury. Hypoxia promotes tubular cell death, fibrosis and CKD progression. Munc18-1-interacting protein 3 (Mint3) is a molecule that activates hypoxia-inducible factors (HIFs) by binding and suppressing factor inhibiting HIF-1 (FIH). However, the role of Mint3 in tubulointerstitial fibrosis remains unknown. Methods We induced fibrosis of the kidney after unilateral ischemia–reperfusion injury (uIRI) in Mint3-knockout and littermate wild-type mice. The duration of ischemia was 23 min and the kidneys were harvested at 24 h and 7 days after ischemia–reperfusion. The function of Mint3 was further investigated by using mouse cortical tubular (MCT) cells, which were treated with Mint3 and/or FIH small interfering RNA and exposed to normoxia or hypoxia. Results Knockout of Mint3 did not affect the acute injury induced by uIRI, but exacerbated the tubulointerstitial fibrosis, accompanied by an increase in TEC apoptosis. Consistently, hypoxia-induced apoptosis of MCT cells was aggravated by Mint3 knockdown. Unexpectedly, the additional knockdown of FIH did not suppress the increase in apoptosis by Mint3 knockdown, demonstrating the irrelevance of the FIH/HIF pathway. Therefore, we next focused on nuclear factor (NF)-κB, which has an anti-apoptotic role. Indeed, not only the expression of the inhibitory NF-κB p50 but also the DNA-binding activity of p50/p50 homodimer was increased by knockdown of Mint3 in the TECs, along with the decreased expressions of the NF-κB-targeted anti-apoptotic genes. An increase in NF-κB p50 was also confirmed in Mint3-knockout kidneys. Conclusions Mint3 in epithelial cells protects the cells from apoptosis by up-regulating anti-apoptotic effects of NF-κB, leading to fibrosis suppression. This new pathophysiology of tubulointerstitial fibrosis could be a target of future therapy for CKD.

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Mukhtarova, A. V., M. M. Batyushin, Е. А. Sinelnik, and N. V. Antipova. "Role of MCP-1 in the development of tubulointerstitial fibrosis in patients with primary chronic glomerulonephritis." Nephrology (Saint-Petersburg) 25, no. 5 (September 2, 2021): 92–98. http://dx.doi.org/10.36485/1561-6274-2021-25-5-92-98.

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BACKGROUND. To date, the study of the factors involved in the glomerular-tubular pathological connections leading to damage to the tubulointerstitial tissue is one of the topical areas of nephrology. THE AIM: to study the effect of MCP-1 in the development of tubulointerstitial fibrosis as a factor in the irreversible progression of chronic renal failure. PATIENTS ANDMETHODS. Prospective observation and retrospective analysis of case histories were carried out, which included a total of 75 patients with primary chronic glomerulonephritis. RESULTS. The average age of the patients was 36.7 ± 12.3 years, of which 52 were males, 23 were women. The average length of service in a nephrological disease was 3.0 [1.0; 5.0] years. The calculated GFR values are 87.3 ± 31.2 ml / min / 1.73 m2. In the general population, the moderate degree of MCP-1 expression, estimated at 2 points, was 35 %, pronounced expression was found in 25 % of the respondents. In the mesangium of the glomeruli and in macrophages, the expressed degree of MCP-1 expression was 20 % and 16 %, respectively, which characterizes MCP-1 as a marker produced by resident cells. When studying the relationship of MCP-1 in blood with clinical parameters, a correlation was found with the values of total protein (Rs= –0.43; p <0.05), with erythrocyturia (Rs= –0.28; p <0.05), as well as with an albumin level (Rs= –0.5; p <0.05), which indicates the role of MCP-1 in the development of nephritic forms of glomerulonephritis. Depending on the severity of MCP-1 expression in biopsy specimens, the incidence of focal tubulointerstitial fibrosis with MCP-1 expression estimated at 1 point was 13.3 %, 2 points – 14.3 %, 3 points – 44.0 %. The revealed significant correlation between the serum level of MCP-1 and the severity of tubulointerstitial fibrosis confirms the MCP-1-mediated mechanism of progression of CKD. CONCLUSION. The relationship of serum and tissue forms of MCP-1 with the progression of tubulointerstitial fibrosis in chronic glomerulonephritis has been demonstrated. MCP-1-induced mesangial cell plays a critical role in the development of renal tubular damage, and its increased expression is associated with progressive tubulointerstitial fibrosis and decreased renal function.

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Schanstra, Joost, Johan Duchene, Laurence Desmond, Eric Neau, Denis Calise, Serge Estaque, Jean-Pierre Girolami, and Jean-Loup Bascands. "The protective effect of angiotensin converting enzyme inhibition in experimental renal fibrosis in mice is not mediated by bradykinin B2 receptor activation." Thrombosis and Haemostasis 89, no. 04 (2003): 735–40. http://dx.doi.org/10.1055/s-0037-1613580.

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SummaryUnilateral ureteral obstruction (UUO) is an animal model of accelerated renal tubulointerstitial fibrosis. We have recently shown, using this model, that mice lacking the bradykinin B2-receptor (B2-/- ) were more susceptible than control animals to the development of tubulointerstitial fibrosis. Angiotensin converting enzyme (ACE) inhibition slows down UUO-induced renal fibrosis. Since ACE-inhibition increases bradykinin and decreases angiotensin II concentrations we have verified if bradykinin is involved in the antifibrotic effects of ACE-inhibition using the UUO-model and B2-/- mice. Surprisingly, although ACE-inhibition significantly reduced renal fibrosis, no difference was observed between the degree of tubulointerstitial fibrosis, macrophage infiltration and cell proliferation between ACE-inhibitor treated B2+/+ and B2-/- mice suggesting the absence of a role of the B2-receptor in the antifibrotic effects of ACE-inhibition. This was confirmed at the level of bradykinin-induced activity of enzymes involved in the degradation of the extracellular matrix. However in both mouse strains, ACE-inhibitors were more efficient than AT1 receptor antagonists.Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

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Wang, Bin, Wei Ding, Minmin Zhang, Hongmei Li, and Yong Gu. "Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis." Cellular Physiology and Biochemistry 35, no. 1 (2015): 116–25. http://dx.doi.org/10.1159/000369680.

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Background/Aim: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. Methods: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. Results: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. Conclusions: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.

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Peng, Wen, Jie Zhao, Li Wang, Aili Cao, Minqian Jiang, and Xia Chen. "Renal Tubulointerstitial Fibrosis: A Review in Animal Models." Journal of Integrative Nephrology and Andrology 2, no. 3 (2015): 75. http://dx.doi.org/10.4103/2225-1243.161428.

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Strutz, Frank. "Pathogenesis of tubulointerstitial fibrosis in chronic allograft dysfunction." Clinical Transplantation 23 (December 2009): 26–32. http://dx.doi.org/10.1111/j.1399-0012.2009.01106.x.

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JUNGTHIRAPANICH, Jaakchai, Vararat SINGKHWA, Dhevy WATANA, Prasit FUTRAKUL, Rachanee SENSIRIVATANA, and Saowanee YENRUDI. "Significance of tubulointerstitial fibrosis in paediatric IgM nephropathy." Nephrology 3, no. 4 (August 1997): 509–14. http://dx.doi.org/10.1111/j.1440-1797.1997.tb00234.x.

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Sato, Norihiro, Kazumi Shiraiwa, Kiyonori Kai, Atsushi Watanabe, Shinichi Ogawa, Yoshiro Kobayashi, Hiroko Yamagishi-Imai, Yasunori Utsunomiya, and Tetsuya Mitarai. "Mizoribine Ameliorates the Tubulointerstitial Fibrosis of Obstructive Nephropathy." Nephron 89, no. 2 (2001): 177–85. http://dx.doi.org/10.1159/000046065.

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Hebiguchi, Tatsuzo, Tetsuo Kato, Hiroaki Yoshino, Masaru Mizuno, Hideki Wakui, Atsushi Komatsuda, and Hirokazu Imai. "Extremely Short Small Bowel Induces Focal Tubulointerstitial Fibrosis." Journal of Pediatric Gastroenterology and Nutrition 32, no. 5 (May 2001): 586–92. http://dx.doi.org/10.1097/00005176-200105000-00018.

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Oba, Shigeyoshi, Shintaro Kumano, Etsu Suzuki, Hiroaki Nishimatsu, Masao Takahashi, Hajime Takamori, Masatoshi Kasuya, et al. "miR-200b Precursor Can Ameliorate Renal Tubulointerstitial Fibrosis." PLoS ONE 5, no. 10 (October 25, 2010): e13614. http://dx.doi.org/10.1371/journal.pone.0013614.

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Burns, Kevin D. "Interleukin-1β as a mediator of tubulointerstitial fibrosis." Kidney International 62, no. 1 (July 2002): 346–47. http://dx.doi.org/10.1046/j.1523-1755.2002.00439.x.

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Qi, Weier, Xinming Chen, Philip Poronnik, and Carol A. Pollock. "The renal cortical fibroblast in renal tubulointerstitial fibrosis." International Journal of Biochemistry & Cell Biology 38, no. 1 (January 2006): 1–5. http://dx.doi.org/10.1016/j.biocel.2005.09.005.

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Chen, Tso-Hsiao, Yuh-Mou Sue, Chung-Yi Cheng, and Cheng-Hsien Chen. "MP061FUCOXANTHIN REDUCES RENAL TUBULOINTERSTITIAL FIBROSIS BY UPREGULATING NHE1." Nephrology Dialysis Transplantation 32, suppl_3 (May 1, 2017): iii448. http://dx.doi.org/10.1093/ndt/gfx162.mp061.

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Pak, Eun Seon, Lak Shin Jeong, Xiyan Hou, Sushil K. Tripathi, Jiyoun Lee, and Hunjoo Ha. "Dual Actions of A2A and A3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice." International Journal of Molecular Sciences 22, no. 11 (May 26, 2021): 5667. http://dx.doi.org/10.3390/ijms22115667.

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Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A1AR, A2AAR, A2BAR, and A3AR. A2AAR agonists protect against inflammation, and A3AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A2AAR agonist and an A3AR antagonist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis.

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Colon, Selene, Haiyan Luan, Yan Liu, Cameron Meyer, Leslie Gewin, and Gautam Bhave. "Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model." American Journal of Physiology-Renal Physiology 316, no. 2 (February 1, 2019): F360—F371. http://dx.doi.org/10.1152/ajprenal.00291.2018.

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Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (H2O2). The animal heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPX), and peroxidasin (PXDN) uniquely metabolize H2O2 into highly reactive and destructive hypohalous acids, such as hypobromous and hypochlorous acid. However, the role of these peroxidases and their downstream hypohalous acids in the pathogenesis of renal fibrosis is unclear. Our study defines the contribution of MPO, EPX, and PXDN to renal inflammation and tubulointerstitial fibrosis in the murine unilateral ureteral obstruction (UUO) model. Using a nonspecific inhibitor of animal heme peroxidases and peroxidase-specific knockout mice, we find that loss of EPX or PXDN, but not MPO, reduces renal fibrosis. Furthermore, we demonstrate that eosinophils, the source of EPX, accumulate in the renal interstitium after UUO. These findings point to EPX and PXDN as potential therapeutic targets for renal fibrosis and CKD and suggest that eosinophils modulate the response to renal injury.

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Wu, Weiju, Chengfei Liu, Conrad A. Farrar, Liang Ma, Xia Dong, Steven H. Sacks, Ke Li, and Wuding Zhou. "Collectin-11 Promotes the Development of Renal Tubulointerstitial Fibrosis." Journal of the American Society of Nephrology 29, no. 1 (November 15, 2017): 168–81. http://dx.doi.org/10.1681/asn.2017050544.

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Collectin-11 is a recently described soluble C-type lectin, a pattern recognition molecule of the innate immune system that has distinct roles in host defense, embryonic development, and acute inflammation. However, little is known regarding the role of collectin-11 in tissue fibrosis. Here, we investigated collectin-11 in the context of renal ischemia-reperfusion injury. Compared with wild-type littermate controls, Collec11 deficient (CL-11−/−) mice had significantly reduced renal functional impairment, tubular injury, renal leukocyte infiltration, renal tissue inflammation/fibrogenesis, and collagen deposition in the kidneys after renal ischemia-reperfusion injury. In vitro, recombinant collectin-11 potently promoted leukocyte migration and renal fibroblast proliferation in a carbohydrate-dependent manner. Additionally, compared with wild-type kidney grafts, CL-11−/−mice kidney grafts displayed significantly reduced tubular injury and collagen deposition after syngeneic kidney transplant. Our findings demonstrate a pathogenic role for collectin-11 in the development of tubulointerstitial fibrosis and suggest that local collectin-11 promotes this fibrosis through effects on leukocyte chemotaxis and renal fibroblast proliferation. This insight into the pathogenesis of tubulointerstitial fibrosis may have implications for CKD mediated by other causes as well.

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Hewitson, T. D., I. A. Darby, T. Bisucci, C. L. Jones, and G. J. Becker. "Evolution of tubulointerstitial fibrosis in experimental renal infection and scarring." Journal of the American Society of Nephrology 9, no. 4 (April 1998): 632–42. http://dx.doi.org/10.1681/asn.v94632.

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Renal tubulointerstitial fibrosis may result from a loss of tubulointerstitial volume, which produces a disproportionate increase in the density of matrix. This study examines the relationship between fibrogenesis and collapse in scar formation after experimental renal infection. Escherichia coli were inoculated into the renal cortex of Sprague Dawley rats, with saline substituted in a control group. Glomerular, tubular, and interstitial profile areas were determined. Density of glomerular profiles was used as a measure of tubulointerstitial collapse. Collagen type I, III, and IV expression was examined by in situ hybridization and immunohistochemistry. Myofibroblasts were identified by alpha smooth muscle actin immunohistochemistry, and matrix metalloproteinase-1 (MMP-1) and MMP-2 were localized with appropriate antisera. Acute interstitial edema was followed by increasing density of glomerular profiles, paralleled by loss of interstitial volume and progressive tubular atrophy. Glomerular profile area remained unchanged. Density of glomerular profiles was not temporally related to myofibroblast accumulation. Procollagen alpha 1(I), alpha 1(III), and alpha 1(IV) transcription was focal, spatially related but temporally ordered. Collagen I, III, and IV immunostaining was increased from days 3, 24, and 100, respectively (P < 0.05 versus day 0 and day 100 saline). However, when corrected for glomerular density, collagen I immunostaining decreased between days 24 and 100, whereas collagen III and IV no longer differed from day 0. MMP staining within the lesion was confined to occasional interstitial and epithelial cells throughout. It is concluded that in this model, contraction and collapse of the tubulointerstitial parenchyma has a greater influence than new collagen production on final fibrotic density.

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KÖKSAL CEVHER, Şimal, Ezgi ÇOŞKUN YENİGÜN, Ramazan ÖZTÜRK, Didem TURGUT, Nihal ÖZKAYAR, Nergiz BAYRAKÇI, and Fatih DEDE. "A Rare Cause of Acute Tubulointerstitial Nephritis: Retroperitoneal Fibrosis: Case Report." Turkiye Klinikleri Journal of Internal Medicine 1, no. 2 (2016): 99–102. http://dx.doi.org/10.5336/intermed.2015-47087.

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An, Won Suk, Hyun Ju Kim, Kyu-Hyang Cho, and Nosratola D. Vaziri. "Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney." American Journal of Physiology-Renal Physiology 297, no. 4 (October 2009): F895—F903. http://dx.doi.org/10.1152/ajprenal.00217.2009.

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Significant reduction of renal mass initiates a series of hemodynamic and nonhemodynamic events which lead to proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal failure. Lipid mediators derived from fatty acids participate in regulation of renal hemodynamic and nonhemodynamic processes that influence progression of renal disease. Composition of cellular fatty acids and hence related signaling responses are influenced by their dietary contents. Consumption of omega-3 fatty acids (O-3FA) has proven effective in mitigating atherosclerosis. We tested the hypothesis that O-3FA supplementation may retard progression and attenuate upregulation of pathways involved in oxidative stress, inflammation, and fibrosis in rats with renal mass reduction. Sprague-Dawley rats were subjected to 5/6 nephrectomy [chronic renal failure (CRF)] and randomly assigned to the untreated and O-3FA-treated (0.3 g·kg−1·day−1 by gastric gavage for 12 wk) groups. Sham-operated rats served as controls. The untreated CRF rats exhibited proteinuria, hypertension, azotemia, upregulations of renal tissue NAD(P)H oxidase, MCP-1, COX-2, PAI-1, TGF-β, Smad2, α-smooth muscle actin, fibronectin, and hepatocyte growth factor, activation of ERK1/2 and NF-κB, downregulation of Smad7, intense mononuclear leukocyte infiltration, tubulointerstitial fibrosis, and glomerulosclerosis. O-3FA supplementation significantly lowered COX-2, NAD(P)H oxidase (NOX-4, gp91phox, p47phox, p22phox), PAI-1, TGF-β, connective tissue growth factor, α-smooth muscle actin, fibronectin, Smad2, and MCP-1, raised Smad7, and attenuated ERK1/2 and NF-κB activation, tubulointerstitial fibrosis, and inflammation. Thus, long-term O-3FA supplementation can reduce or reverse upregulation of prooxidant, proinflammatory, and profibrotic pathways and attenuate tubulointerstitial fibrosis in the remnant kidney.

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Hamar, Péter, and Dontscho Kerjaschki. "Blood capillary rarefaction and lymphatic capillary neoangiogenesis are key contributors to renal allograft fibrosis in an ACE inhibition rat model." American Journal of Physiology-Heart and Circulatory Physiology 311, no. 4 (October 1, 2016): H981—H990. http://dx.doi.org/10.1152/ajpheart.00320.2016.

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Chronic allograft fibrosis is the major cause of graft loss in kidney transplantation. Progression can only be reduced by inhibition of the renin-angiotensin system (RAS). We tested the hypothesis that the protection provided by angiotensin-converting enzyme (ACE) inhibition also decreases capillary rarefaction, lymphangiogenesis, and podocyte injury in allograft fibrosis. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats treated with enalapril (60 mg/kg per day) (ACE inhibitor, ACEi) or vehicle. Proteinuria, blood urea nitrogen, and plasma creatinine were regularly assessed, and grafts were harvested for morphological and immunohistological analysis at various times up to 32 wk. In the vehicle group, many new lymphatic capillaries and severe and diffuse mononuclear infiltration of allografts were observed already 1 wk after transplantation. Lymphangiogenesis increased until week 4, by which time inflammatory infiltration became focal. Lymphatic capillaries were often located at sites of inflammation. Progressive interstitial fibrosis, glomerulosclerosis, capillary rarefaction, and proteinuria appeared later, at weeks 4–12. The number of lymphatic capillary cross sections strongly correlated with the interstitial fibrosis score. Podoplanin immunostaining, a marker of healthy podocytes, disappeared from inflamed or sclerotic glomerular areas. ACEi protected from lymphangiogenesis and associated inflammation, preserved glomerular podoplanin protein expression, and reduced glomerulosclerosis, proteinuria, tubulointerstitial fibrosis, and blood capillary rarefaction at 32 wk. In conclusion, ACEi considerably decreased and/or delayed both glomerulosclerosis and tubulointerstitial injury. Prevention of glomerular podoplanin loss and proteinuria could be attributed to the known intraglomerular pressure-lowering effects of ACEi. Reduction of lymphangiogenesis could contribute to amelioration of tubulointerstitial fibrosis and inflammatory infiltration after ACEi.

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Tian, Shaojiang, Guohua Ding, Ruhan Jia, and Guili Chu. "Tubulointerstitial Macrophage Accumulation is Regulated by Sequentially Expressed Osteopontin and Macrophage Colony-Stimulating Factor: Implication for the Role of Atorvastatin." Mediators of Inflammation 2006 (2006): 1–9. http://dx.doi.org/10.1155/mi/2006/12919.

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Infiltration and local proliferation are known factors that contribute to tubulointerstitial macrophage accumulation. This study explored the time course of these two contributors' roles as tubulointerstitial inflammation and fibrosis progressing, and evaluated the mechanisms of the protective effect of atorvastatin. Unilateral ureteral obstructive (UUO) rats were treated with atorvastatin (10 mg/Kg) or vehicle. Expression of osteopontin (OPN) and macrophage colony-stimulating factor (M-CSF) was evaluated by RT-PCR and immunohistochemistry. Immunohistochemistry staining of ED1 was used to assess macrophage accumulation in interstitium. Histological evaluation was performed to semiquantify tubulointerstitial fibrosis. The results showed that on day 3 after UUO operation, OPN expression significantly increased and positively correlated with the number of the interstitial ED1+cells, while on day 10, M-CSF expression upregulated and correlated with interstitial ED1+cells. In atorvastatin treatment group, the increments of these two factors were attenuated significantly at the two time points, respectively. ED1+cell accumulation and fibrosis also ameliorated in the treatment group. For all the samples of UUO and treatment group on day 10, ED1+cells also correlated with interstitial fibrosis scores. The results suggest that OPN may induce the early macrophage/monocyte infiltration and M-CSF may play an important role in regulating macrophage accumulation in later stage of UUO nephropathy. Statin treatment decreases interstitial inflammation and fibrosis, and this renoprotective effect may be mediated by downregulating the expression of OPN and M-CSF.

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Maksimowski, Nicholas A., James W. Scholey, and Vanessa R. Williams. "Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study." PLOS ONE 16, no. 6 (June 7, 2021): e0252758. http://dx.doi.org/10.1371/journal.pone.0252758.

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Background Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. Methods We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. Results ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. Conclusions Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.

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Schaier, Matthias, Stefanie Vorwalder, Claudia Sommerer, Ralf Dikow, Friederike Hug, Marie-Luise Gross, Rüdiger Waldherr, and Martin Zeier. "Role of FTY720 on M1 and M2 macrophages, lymphocytes, and chemokines in \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({5}/{6}\) \end{document} nephrectomized rats." American Journal of Physiology-Renal Physiology 297, no. 3 (September 2009): F769—F780. http://dx.doi.org/10.1152/ajprenal.90530.2008.

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Renal injury is accompanied by the presence of infiltrating inflammatory cells in the glomerulus and tubulointerstitium. FTY720 modifies lymphocyte migration into injured tissues by lymphocyte sequestration to secondary lymphoid organs. The purpose of this study was to examine the potential of FTY720 to influence the inflammatory response in a nonimmunological model of renal failure. Sham-operated and [Formula: see text] nephrectomized (SNX) Sprague-Dawley rats received two different doses of FTY720 or vehicle orally for 14 wk. Treatment with FTY720 reduced glomerular and tubulointerstitial damage in SNX rats but failed to stabilize creatinine clearance. The increase in gene expression of chemokine receptors CCR1, CCR2, and CCR5 in kidneys of vehicle-treated SNX rats was significantly attenuated by high-dose FTY720. Treatment with high-dose FTY720 tended to normalize RANTES and MCP-1 renal gene expression. FTY720 affected not only glomerular and tubulointerstitial lymphocytes, but M1 and M2 phenotype macrophages were also reduced. FTY720 significantly reduced key mediators of renal inflammation and fibrosis. FTY720 also decreased immunoregulation of M2 macrophages, which are beneficial for tissue remodeling and repair.

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Jin, Jixiu, Tian Wang, Woong Park, Wenjia Li, Won Kim, Sung Kwang Park, and Kyung Pyo Kang. "Inhibition of Yes-Associated Protein by Verteporfin Ameliorates Unilateral Ureteral Obstruction-Induced Renal Tubulointerstitial Inflammation and Fibrosis." International Journal of Molecular Sciences 21, no. 21 (October 31, 2020): 8184. http://dx.doi.org/10.3390/ijms21218184.

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Yes-associated protein (YAP) activation after acute ischemic kidney injury might be related to interstitial fibrosis and impaired renal tubular regeneration. Verteporfin (VP) is a photosensitizer used in photodynamic therapy to treat age-related macular degeneration. In cancer cells, VP inhibits TEA domain family member (TEAD)-YAP interactions without light stimulation. The protective role of VP in unilateral ureteral obstruction (UUO)-induced renal fibrosis and related mechanisms remains unclear. In this study, we investigate the protective effects of VP on UUO-induced renal tubulointerstitial inflammation and fibrosis and its regulation of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We find that VP decreased the UUO-induced increase in tubular injury, inflammation, and extracellular matrix deposition in mice. VP also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells by modulating Smad2 and Smad3 phosphorylation. Therefore, YAP inhibition might have beneficial effects on UUO-induced tubulointerstitial inflammation and fibrosis by regulating the TGF-β1/Smad signaling pathway.

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Guo, Honglei, Xiao Bi, Ping Zhou, Shijian Zhu, and Wei Ding. "NLRP3 Deficiency Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease." Mediators of Inflammation 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/8316560.

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Background and Aims. The nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome has been implicated in the pathogenesis of chronic kidney disease (CKD); however, its exact role in glomerular injury and tubulointerstitial fibrosis is still undefined. The present study was performed to identify the function of NLRP3 in modulating renal injury and fibrosis and the potential involvement of mitochondrial dysfunction in the murine unilateral ureteral obstruction (UUO) model of CKD. Methods. Employing wild-type (WT) and NLRP3−/− mice with or without UUO, we evaluated renal structure, tissue injury, and mitochondrial ultrastructure, as well as expression of some vital molecules involved in the progression of fibrosis, apoptosis, inflammation, and mitochondrial dysfunction. Results. The severe glomerular injury and tubulointerstitial fibrosis induced in WT mice by UUO was markedly attenuated in NLRP3−/− mice as evidenced by blockade of extracellular matrix deposition, decreased cell apoptosis, and phenotypic alterations. Moreover, NLRP3 deletion reversed UUO-induced impairment of mitochondrial morphology and function. Conclusions. NLRP3 deletion ameliorates mitochondrial dysfunction and alleviates renal fibrosis in a murine UUO model of CKD.

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You, Ran, Wei Zhou, Yanwei Li, Yue Zhang, Songming Huang, Zhanjun Jia, and Aihua Zhang. "Inhibition of ROCK2 alleviates renal fibrosis and the metabolic disorders in the proximal tubular epithelial cells." Clinical Science 134, no. 12 (June 2020): 1357–76. http://dx.doi.org/10.1042/cs20200030.

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Abstract Non-specific inhibition of Rho-associated kinases (ROCKs) alleviated renal fibrosis in the unilateral ureteral obstruction (UUO) model, while genetic deletion of ROCK1 did not affect renal pathology in mice. Thus, whether ROCK2 plays a role in renal tubulointerstitial fibrosis needs to be clarified. In the present study, a selective inhibitor against ROCK2 or genetic approach was used to investigate the role of ROCK2 in renal tubulointerstitial fibrosis. In the fibrotic kidneys of chronic kidney diseases (CKDs) patients, we observed an enhanced expression of ROCK2 with a positive correlation with interstitial fibrosis. In mice, the ROCK2 protein level was time-dependently increased in the UUO model. By treating CKD animals with KD025 at the dosage of 50 mg/kg/day via intraperitoneal injection, the renal fibrosis shown by Masson’s trichrome staining was significantly alleviated along with the reduced expression of fibrotic genes. In vitro, inhibiting ROCK2 by KD025 or ROCK2 knockdown/knockout significantly blunted the pro-fibrotic response in transforming growth factor-β1 (TGF-β1)-stimulated mouse renal proximal tubular epithelial cells (mPTCs). Moreover, impaired cellular metabolism was reported as a crucial pathogenic factor in CKD. By metabolomics analysis, we found that KD025 restored the metabolic disturbance, including the impaired glutathione metabolism in TGF-β1-stimulated tubular epithelial cells. Consistently, KD025 increased antioxidative stress enzymes and nuclear erythroid 2-related factor 2 (Nrf2) in fibrotic models. In addition, KD025 decreased the infiltration of macrophages and inflammatory response in fibrotic kidneys and blunted the activation of macrophages in vitro. In conclusion, inhibition of ROCK2 may serve as a potential novel therapy for renal tubulointerstitial fibrosis in CKD.

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Xavier, Sandhya, Ranjit K. Sahu, Susan G. Landes, Jing Yu, Ronald P. Taylor, Srinivas Ayyadevara, Judit Megyesi, et al. "Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis." American Journal of Physiology-Renal Physiology 312, no. 3 (March 1, 2017): F516—F532. http://dx.doi.org/10.1152/ajprenal.00604.2016.

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We have examined the pathogenic role of increased complement expression and activation during kidney fibrosis. Here, we show that PDGFRβ-positive pericytes isolated from mice subjected to obstructive or folic acid injury secrete C1q. This was associated with increased production of proinflammatory cytokines, extracellular matrix components, collagens, and increased Wnt3a-mediated activation of Wnt/β-catenin signaling, which are hallmarks of myofibroblast activation. Real-time PCR, immunoblots, immunohistochemistry, and flow cytometry analysis performed in whole kidney tissue confirmed increased expression of C1q, C1r, and C1s as well as complement activation, which is measured as increased synthesis of C3 fragments predominantly in the interstitial compartment. Flow studies localized increased C1q expression to PDGFRβ-positive pericytes as well as to CD45-positive cells. Although deletion of C1qA did not prevent kidney fibrosis, global deletion of C3 reduced macrophage infiltration, reduced synthesis of C3 fragments, and reduced fibrosis. Clodronate mediated depletion of CD11bF4/80 high macrophages in UUO mice also reduced complement gene expression and reduced fibrosis. Our studies demonstrate local synthesis of complement by both PDGFRβ-positive pericytes and CD45-positive cells in kidney fibrosis. Inhibition of complement activation represents a novel therapeutic target to ameliorate fibrosis and progression of chronic kidney disease.

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Vidyasagar, Aparna, Shannon Reese, Zeki Acun, Debra Hullett, and Arjang Djamali. "HSP27 is involved in the pathogenesis of kidney tubulointerstitial fibrosis." American Journal of Physiology-Renal Physiology 295, no. 3 (September 2008): F707—F716. http://dx.doi.org/10.1152/ajprenal.90240.2008.

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We hypothesized that heat shock protein 27 (HSP27), a small heat shock protein with actin-remodeling properties, is involved in the pathogenesis of kidney tubulointerstitial fibrosis. We first examined its expression in the rat unilateral ureteral obstruction (UUO) model of kidney fibrosis and epithelial-to-mesenchymal transition (EMT). Immunoblot analyses showed that UUO resulted in significant upregulation of TGF-β1, α-smooth muscle actin (α-SMA), total and phosphorylated HSP27, and phosphorylated p38MAPK. Immunofluorescence studies showed that HSP27 costained with TGF-β1, α-SMA, and E-cadherin in areas of tubulointerstitial injury. We next attempted to translate these studies in an in vitro model of EMT using rat proximal tubular epithelial cells (NRK52E). TGF-β1 (20 ng/ml) treatment resulted in EMT (upregulation of α-SMA and downregulation of E-cadherin) and significant upregulation of total and phosphorylated HSP27 and p38MAPK after 3 days. Real-time PCR analyses showed that HSP27, vimentin, and fibronectin increased whereas E-cadherin mRNA levels decreased. Double-staining immunofluorescence studies showed intracytoplasmic colocalization of HSP27 with both F-actin and E-cadherin in cells undergoing EMT. HSP27 overexpression by transient transfection significantly increased E-cadherin while decreasing E-cadherin repressor Snail levels. In aggregate, these studies show that HSP27 is involved in the pathogenesis of TGF-β1-induced EMT and chronic tubulointerstitial fibrosis. HSP27 overexpression may delay injury by upregulating E-cadherin through downregulation of Snail.

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Morrissey, J. J., S. Ishidoya, R. McCracken, and S. Klahr. "Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy." Journal of the American Society of Nephrology 7, no. 10 (October 1996): 2202–12. http://dx.doi.org/10.1681/asn.v7102202.

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Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.

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Cina, Davide P., Hui Xu, Limin Liu, Laszlo Farkas, Daniela Farkas, Martin Kolb, and Peter J. Margetts. "Renal tubular angiogenic dysregulation in anti-Thy1.1 glomerulonephritis." American Journal of Physiology-Renal Physiology 300, no. 2 (February 2011): F488—F498. http://dx.doi.org/10.1152/ajprenal.00214.2010.

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Peritubular vascular changes and hypoxia after glomerular injury may explain subsequent tubulointerstitial injury and fibrosis. Several studies suggested that the expected tubulointerstitial angiogenic response is actively suppressed in this setting. The mechanism of this aberrant response has not been clearly identified. We used a common model of glomerular injury in rats to assess vascular changes and to identify potential factors associated with this aberrant response. Anti-Thy1.1 antibody administration (1 or 4 weekly doses) led to a dose-dependent renal damage characterized by elevated urea and tubulointerstitial fibrosis as assessed by Picro-Sirius Red staining. We quantified peritubular capillaries using CD31 and CD34 immunohistochemistry and showed that tubular angiogenic dysregulation was associated with peritubular capillary rarefaction. Using laser capture microdissection, we demonstrated an early induction of fibrogenic and angiogenic factors in the glomeruli and a subsequent dysregulated angiogenic response in the tubulointerstitial compartment. Proximal tubules of anti-Thy1.1-treated animals had increased pigment epithelial-derived factor (PEDF) expression by immunohistochemistry. Protein taken by laser capture microdissection also showed that PEDF was upregulated. Temporally associated with PEDF expression was a transient downregulation of tubular hypoxia-inducible factor (HIF)1α. In a human proximal tubular cell culture, we show that PEDF downregulates HIF1α protein and gene expression in cells exposed to 1% oxygen. In anti-Thy1.1 glomerulonephritis, there is aberrent tubular angiogenesis associated with glomerular injury and tubulointersititial fibrosis. We showed that PEDF may be involved by downregulating HIF1α. Further work is needed to elucidate the mechanism of PEDF upregulation and action in the tubules.

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Ma, Ze-jun, Xiao-na Zhang, Li Li, Wei Yang, Shan-shan Wang, Xin Guo, Pei Sun, and Li-ming Chen. "Tripterygium Glycosides Tablet Ameliorates Renal Tubulointerstitial Fibrosis via the Toll-Like Receptor 4/Nuclear Factor Kappa B Signaling Pathway in High-Fat Diet Fed and Streptozotocin-Induced Diabetic Rats." Journal of Diabetes Research 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/390428.

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Tripterygium glycosides tablet (TGT) is a Chinese traditional medicine that has been shown to protect podocytes from injury and reduce the proteinuria. The aim of this study was to assess the effect of TGT on renal tubulointerstitial fibrosis and its potential mechanism in high-fat diet fed and STZ-induced diabetic rats. Rats were randomly divided into normal control rats (NC group), diabetic rats without drug treatment (DM group), and diabetic rats treated with TGT (1, 3, or 6 mg/kg/day, respectively) for 8 weeks. The results showed that 24 h proteinuria and urinary N-acetyl-glucosaminidase (NAG) in diabetic rats were decreased by TGT treatment without affecting blood glucose. Masson’s trichrome stains showed that apparent renal tubulointerstitial fibrosis was found in DM group, which was ameliorated by TGT treatment. The expression ofα-SMA was significantly decreased, accompanied by increased expression of E-cadherin in TGT-treated rats, but not in untreated DM rats. Further studies showed that TGT administration markedly reduced expression of TLR4, NF-κB, IL-1β, and MCP-1 in TGT-treated diabetic rats. These results showed that TGT could ameliorate renal tubulointerstitial fibrosis, the mechanism which may be at least partly associated with the amelioration of EMT through suppression of the TLR4/NF-κB pathway.

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Prakash, Jai, Klaas Poelstra, Harry Goor, Frits Moolenaar, Dirk Meijer, and Robbert Kok. "Novel Therapeutic Targets for the Treatment of Tubulointerstitial Fibrosis." Current Signal Transduction Therapy 3, no. 2 (May 1, 2008): 97–111. http://dx.doi.org/10.2174/157436208784223161.

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Journal articles on the topic 'Tubulointerstitial fibrosis'

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