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

Ca²⁺-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 Ca²⁺-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 Ca²⁺ concentration ([Ca²⁺]_i), whereas the PIEZO1 activator Yoda1 increased [Ca²⁺]_i and BK channel activity. CCDs from mice fed a high-K⁺ (HK) diet exhibited a greater Yoda1-dependent increase in [Ca²⁺]_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 [Ca²⁺]_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 Ca²⁺ entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.