Piezo1 channel in renal medullary telocytes as a mechanosensor for exosome-dependent blood pressure regulation

The renal medulla plays a critical role in the kidney's compensatory response to elevated renal perfusion pressure (RPP) and extracellular fluid volume, contributing to long-term regulation of arterial blood pressure (BP). A key physiological mechanism in this process is pressure natriuresis, whereby increased RPP promotes sodium excretion. However, the molecular mechanisms by which the renal medulla senses elevated RPP and coordinates tubular sodium handling remain poorly understood. Given that Piezo1 is a mechanosensitive ion channel activated by various mechanical forces and its activation facilitates calcium ion influx to initiate diverse intracellular signaling pathways, we hypothesized Piezo1 channels in renal medullary telocytes are essential for BP regulation through mechanosensing and exosome-mediated natriuresis. To test this hypothesis, we developed a telocyte-specific Piezo1 gene knockout (Piezo1fl/fl/Telocre) mouse strain. After WT/WT and Piezo1fl/fl/Telocre mice were fed either a normal diet or a high-salt diet (HSD, 4% NaCl) for 3 weeks, telemetry BP recording showed that telocyte-specific Piezo1 knockout significantly exaggerated HSD-induced BP elevation in Piezo1fl/fl/Telocre mice compared to WT/WT mice. By nanoparticle tracking analysis, we found that HSD treatment induced a significant elevation in plasma exosome concentration in WT/WT mice, but not in Piezo1fl/fl/Telocre mice. Immunohistochemistry of CD63, an exosome marker, in kidney sections showed that HSD treatment remarkably elevated exosomes in renal medullary interstitial space of WT/WT mice, but not in Piezo1fl/fl/Telocre mice. In pressure natriuresis experiments, elevating RPP robustly increased urine volume and sodium excretion in mice, which was remarkably inhibited by telocyte-specific Piezo1 knockout or intravenous infusion of GsMTx4, a Piezo1 channel inhibitor. In volume expansion studies, acute sodium loading significantly increased urine volume and sodium excretion in WT/WT mice. On the contrary, these responses were blunted in Piezo1fl/fl/Telocre mice and WT/WT mice intravenously infused with GsMTx4, indicating impaired acute natriuretic capacity. In vitro, we demonstrated that Yoda1, a Piezo1 channel agonist, dose-dependently enhanced exosome release from cultured murine renal medullary telocytes. When the mechanical stretching was added on telocytes by 5% circumferential radius elongation of culture plates using Flexcell system, we observed remarkable increase in exosome release from telocytes, which was blocked by pre-treatment with GsMTx4. Moreover, co-infusion of the stretched telocyte-derived exosomes with angiotensin II exerted a significant antihypertensive effect, inhibiting the angiotensin II-induced BP elevation and elevating urine volume and sodium excretion. Taken together, our findings suggest that Piezo1 channel plays a vital role in mechanosensing and antihypertensive exosome release in renal medullary telocytes for BP regulation. Dysfunction or deficiency of Piezo1 in renal medullary telocytes may impair pressure natriuresis and thereby exaggerate salt-sensitive hypertension under pathological conditions Supported by NIH grants DK054927, DK120491, and DK140219. 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.