Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis, blood volume, and pressure. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin that we hypothesized would be mediated by one or more mechanically activated nonselective cation channel. Prior to this study, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS was unclear. As such, the primary goal of our study was to identify a physiologically salient ion channel contributing to renin control in the kidneys. Here, we identified PIEZO2 as a key mechanosensitive ion channel expressed in the renin-producing juxtaglomerular granular cells of the kidneys. We found that conditional genetic loss-of-function of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage or the developing or adult stromal cells dysregulated the RAAS by elevating renin in mice. Consistent with the physiological roles of renin, we found that PIEZO2 regulates the RAAS during acute and chronic blood volume challenges. We observed that PIEZO2 is required for the calcium oscillations of juxtaglomerular granular cells in vivo. Notably, PIEZO2 deficiency in cells of renin lineage drives renin- and MAS Receptor-dependent glomerular hyperfiltration and is associated with increased afferent arteriole diameters. Collectively, our work identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin in vivo. Disclosure of funding sources: The experiments performed in this study were supported by NIH K99NS133478 (to RZH); AHA 20CDA35320169, NIH K01DK121737, The Collins Medical Trust, and ASN KidneyCure (to JWN); 5R01DK097598 (to SJS); NIH R01HL148044 (to MSSL) NIH R01DK132066 (to JAM); NIH R01DK128660 and R01DK141178 (to JHM); NIH R01DK064324 and S10OD021833 (to JP); and a Howard Hughes Medical Institute Investigator Award (to AP). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Hill et al. (Fri,) studied this question.