Podocyte-specific deletion of mechanochannel Piezo1 exacerbates proteinuria and podocyte injury in mouse hypertensive nephropathy

Abstract

Piezo1 is a mechanosensitive ion channel that mediates a broad range of biological and pathological phenomena in living organisms, including hypertension and hypertensive nephropathy. We previously reported the upregulation of Piezo1 in the glomerular podocytes of hypertensive nephropathy mice in vivo and a mechanical stretch-induced podocyte injury cascade via Piezo1 and Rac1 in vitro, suggesting the pathogenic involvement of Piezo1. However, recent reports on podocyte-specific Piezo1 knockout mice with various podocyte injury models other than hypertension have yielded inconsistent results, indicating pathogenic and anti-pathogenic roles of Piezo1. In this study, we generated podocyte-specific Piezo1 knockout mice and examined their podocyte phenotypes under normotensive and hypertensive conditions induced by angiotensin II and a high-salt diet. Podocyte-specific Piezo1 knockout mice did not spontaneously develop podocyte injury. Angiotensin II infusion and a high-salt diet for 14 days caused hypertension, but not significant podocyte injury and proteinuria in the littermate control mice, which were strengthened by podocyte-specific Piezo1 deletion. Through comprehensive transcriptome analysis of the glomeruli of wild-type and podocyte-specific Piezo1 knockout mice, we found altered expression of several genes, including Rhpn1 encoding Rho GTPase binding protein Rhophilin1. Podocyte injury in hypertensive podocyte-specific Piezo1 knockout mice was inhibited by the angiotensin II receptor blocker losartan, the anti-hypertensive drug hydralazine, and partially ameliorated by the Rho kinase inhibitor fasudil, suggesting that podocyte injury in the knockout mice may be mediated by Rhophilin1 and/or Rho signaling downstream of Piezo1. Findings related to the hypertensive podocyte injury model support the possible anti-pathogenic protective roles of Piezo1. We created podocyte-specific Piezo1 KO mice, and hypertension was induced by angiotensin II and a high-salt diet. Hypertension-evoked proteinuria and podocyte injury were exaggerated in the KO mice. They were ameliorated by anti-hypertensive drugs and Rho kinase inhibitor, suggesting protective roles of Piezo1 and involvement of RhoA signaling.

Keywords: Piezo1; RhoA signaling; Rhophilin1; hypertensive nephropathy; podocyte injury.