Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal...

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Bibliographic Details
Published in:	Journal of cellular and molecular medicine Vol. 23; no. 2; pp. 1268 - 1279
Main Authors:	Waasdorp, Maaike, de Rooij, Dennis M., Florquin, Sandrine, Duitman, JanWillem, Spek, C. Arnold
Format:	Journal Article
Language:	English
Published:	England John Wiley & Sons, Inc 01.02.2019 John Wiley and Sons Inc
Subjects:	Acute Kidney Injury - etiology Acute Kidney Injury - metabolism Acute Kidney Injury - pathology Animals Chronic Disease Epithelial cells Epithelial-Mesenchymal Transition epithelial‐to‐mesenchymal transition Fibroblasts Fibrosis Fibrosis - etiology Fibrosis - metabolism Fibrosis - pathology Kidney Diseases - physiopathology Macrophages Mesenchyme Mice Mice, Inbred C57BL Mice, Knockout Nephritis, Interstitial - etiology Nephritis, Interstitial - metabolism Nephritis, Interstitial - pathology Nephropathy obstructive nephropathy Original protease‐activated receptor‐1 Proteinase Receptor, PAR-1 - physiology Renal failure renal fibrosis Rodents Signal Transduction Transforming Growth Factor beta1 - metabolism unilateral ureter obstruction Ureter Ureteral Obstruction - complications United States > US Netherlands protease-activated receptor-1 renal fibrosis unilateral ureter obstruction obstructive nephropathy epithelial-to-mesenchymal transition
ISSN:	1582-1838, 1582-4934, 1582-4934
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Summary:	End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease‐activated receptor (PAR)‐1, which recently emerged as an inducer of epithelial‐to‐mesenchymal transition (EMT), aggravates renal fibrosis. We show that PAR‐1 activation on TECs reduces the expression of epithelial markers and simultaneously induces mesenchymal marker expression reminiscent of EMT. We next show that kidney damage was reduced in PAR‐1‐deficient mice during unilateral ureter obstruction (UUO) and that PAR‐1‐deficient mice develop a diminished fibrotic response. Importantly, however, we did hardly observe any signs of mesenchymal transition in both wild‐type and PAR‐1‐deficient mice suggesting that diminished fibrosis in PAR‐1‐deficient mice is not due to reduced EMT. Instead, the accumulation of macrophages and fibroblasts was significantly reduced in PAR‐1‐deficient animals which were accompanied by diminished production of MCP‐1 and TGF‐β. Overall, we thus show that PAR‐1 drives EMT of TECs in vitro and aggravates UUO‐induced renal fibrosis although this is likely due to PAR‐1‐dependent pro‐fibrotic cytokine production rather than EMT.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 JanWillem Duitman and C. Arnold Spek contributed equally to this work
ISSN:	1582-1838 1582-4934 1582-4934
DOI:	10.1111/jcmm.14028