PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion

Abstract

Ca 2+ -activated BK channels in renal intercalated cells (ICs) mediate luminal flow–induced K + secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca 2+ -permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca 2+ concentration ([Ca 2+ ] i ), whereas the PIEZO1 activator Yoda1 increased [Ca 2+ ] i and BK channel activity. CCDs from mice fed a high-K + (HK) diet exhibited a greater Yoda1-dependent increase in [Ca 2+ ] i than CCDs from mice fed a control K + diet. ICs in CCDs isolated from mice with a targeted gene deletion of Piezo1 in ICs (IC- Piezo1 -KO) exhibited a blunted [Ca 2+ ] i response to Yoda1 or increased flow, with an associated loss of FIKS in CCDs. Male IC- Piezo1 -KO mice selectively exhibited an increased blood [K + ] in response to an oral K + bolus and blunted urinary K + excretion following a volume challenge. Whole-cell expression of BKα subunit was reduced in ICs of IC- Piezo1 -KO mice fed an HK diet. We conclude that PIEZO1 mediates flow-induced basolateral Ca 2+ entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.