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

• Published in: Journal of cellular and molecular medicine 2019-02, Vol.23 (2), p.1268-1279
• Main Authors: Waasdorp, Maaike, de Rooij, Dennis M., Florquin, Sandrine, Duitman, JanWillem, Spek, C. Arnold
• Format: Article
• Language: English
• 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; Kidneys; Macrophages; Mesenchyme; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephritis, Interstitial - etiology; Nephritis, Interstitial - metabolism; Nephritis, Interstitial - pathology; Nephropathy; obstructive nephropathy; Original; Protease; 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
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.14028

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.