Microvesicles containing miR-34a induce apoptosis of proximal tubular epithelial cells and participate in renal interstitial fibrosis

Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and α-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.

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Inhibition of fibroblast growth factor-inducible 14 (Fn14) attenuates experimental tubulointerstitial fibrosis and profibrotic factor expression of proximal tubular epithelial cells

10.21203/rs.3.rs-117045/v1 ◽

2020 ◽

Author(s):

Mai Luo ◽

Mengmeng Liu ◽

Wei Liu ◽

Xiao Cui ◽

Siyue Zhai ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Fibroblast Growth Factor ◽

Interstitial Fibrosis ◽

Tubulointerstitial Fibrosis ◽

Fibroblast Growth ◽

Tubular Epithelial Cells ◽

Matrix Deposition ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular

Abstract As a proinflammatory cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in the progression of renal fibrosis by engaging its receptor, fibroblast growth factor-inducible 14 (Fn14). However, the effect of Fn14 inhibition on tubular epithelial cell-mediated tubulointerstitial fibrosis remains unclear. This study was designed to elucidate the role of TWEAK/Fn14 interaction in the development of experimental tubulointerstitial fibrosis as well as the protective effect of Fn14 knockdown on proximal tubular epithelial cells. A murine model of unilateral ureteral obstruction was constructed in both wild-type and Fn14-deficient BALB/c mice, followed by observation of the tubulointerstitial pathologies. Fn14 deficiency ameliorated the pathological changes, including inflammatory cell infiltration and cell proliferation, accompanied by reduced production of profibrotic factors and extracellular matrix deposition. In vitro experiments showed that TWEAK dose-dependently enhanced the expressions of collagen I, fibronectin, and α-smooth muscle actin in proximal tubular epithelial cells. Interestingly, TWEAK also upregulated the expression levels of Notch1/Jagged1. Fn14 knockdown and Notch/Jagged1 inhibition also mitigated the effect of TWEAK on these cells. In conclusion, TWEAK/Fn14 signals contributed to tubulointerstitial fibrosis by acting on proximal tubular epithelial cells. Fn14 inhibition might be a therapeutic strategy for protecting against renal interstitial fibrosis.

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Osteopontin: correlation with interstitial fibrosis in human diabetic kidney and PI3-kinase-mediated enhancement of expression by glucose in human proximal tubular epithelial cells

Histopathology ◽

10.1111/j.1365-2559.2004.01771.x ◽

2004 ◽

Vol 44 (2) ◽

pp. 136-146 ◽

Cited By ~ 29

Author(s):

A Junaid ◽

F M Amara

Keyword(s):

Epithelial Cells ◽

Interstitial Fibrosis ◽

Pi3 Kinase ◽

Tubular Epithelial Cells ◽

Diabetic Kidney ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular

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The role played by endocytosis in albumin-induced secretion of TGF-β1 by proximal tubular epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00069.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. F1464-F1470 ◽

Cited By ~ 41

Author(s):

Ramaswamy Diwakar ◽

Alex L. Pearson ◽

Paul Colville-Nash ◽

Nigel J. Brunskill ◽

Mark E. C. Dockrell

Keyword(s):

Epithelial Cells ◽

Inflammatory Responses ◽

Cell Clone ◽

Interstitial Fibrosis ◽

Apical Surface ◽

Tubular Epithelial Cells ◽

Opossum Kidney ◽

Proximal Tubular Epithelial Cells ◽

Proximal Tubular ◽

Albumin Endocytosis

Proteinuria predicts the decline of renal function in chronic kidney disease. Reducing albuminuria has been shown to be associated with a reduction in this rate of decline. Proximal tubular epithelial cells (PTECs), when exposed to albumin produce matrix proteins, proinflammatory and profibrotic cytokines like TGF-β1. Some of these effects are dependent on endocytosis of albumin by PTECs. However, conditions like diabetic nephropathy, believed to be associated with reduced albumin endocytosis, are associated with interstitial fibrosis. Moreover, megalin, the putative albumin binding receptor in PTECs, has potential signaling motifs in its cytoplasmic domain, suggesting its ability to signal in response to ligand binding from the apical surface of PTECs. Hence, we looked to see whether albumin-induced secretion of TGF-β1 by PTECs is dependent on albumin endocytosis or whether it could occur in the absence of albumin endocytosis. We studied the production of TGF-β1 in two accepted models of PTECs, opossum kidney cells and human kidney cell clone-8 cells, with widely varying degrees of endocytosis. We then studied the effect of inhibiting albumin endocytosis with various inhibitors on albumin-induced TGF-β1 secretion. Our results indicate that albumin-induced TGF-β1 secretion by PTECs does not require albumin endocytosis and therefore the mechanism for the induction of some profibrotic responses by albumin may differ from those required for some of the inflammatory responses. Moreover, we found that albumin-induced TGF-β1 secretion by PTECs is not dependent on its interaction with megalin.

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