TRPV4 deletion protects against hypokalemia during systemic K⁺ deficiency

Tight regulation of K⁺ balance is fundamental for normal physiology. Reduced dietary K⁺ intake, which is common in Western diets, often leads to hypokalemia and associated cardiovascular-and kidney-related pathologies. The distal nephron, and, specifically, the collecting duct (CD), is the major site of controlled K⁺ reabsorption via H⁺-K⁺-ATPase in the state of dietary K⁺ deficiency. We (Mamenko MV, Boukelmoune N, Tomilin VN, Zaika OL, Jensen VB, O’Neil RG, Pochynyuk OM. Kidney Int 91: 1398–1409, 2017) have previously demonstrated that the transient receptor potential vanilloid type 4 (TRPV4) Ca²⁺ channel, abundantly expressed in the CD, contributes to renal K⁺ handling by promoting flow-induced K⁺ secretion. Here, we investigated a potential role of TRPV4 in controlling H⁺-K⁺-ATPase-dependent K⁺ reabsorption in the CD. Treatment with a K⁺-deficient diet (±0.01% K⁺) for 7 days reduced serum K⁺ levels in wild-type (WT) mice from 4.3 = 0.2 to 3.3 = 0.2 mM but not in TRPV4^-/- mice (4.3 = 0.1 and 4.2 = 0.3 mM, respectively). Furthermore, we detected a significant reduction in 24-h urinary K⁺ levels in TRPV4^-/- compared with WT mice upon switching to K⁺-deficient diet. TRPV4^-/- animals also had significantly more acidic urine on a low-K⁺ diet, but not on a regular (0.9% K⁺)or high-K⁺ (5% K⁺) diet, which is consistent with increased H⁺-K⁺-ATPase activity. Moreover, we detected a greatly accelerated H⁺-K⁺-ATPase-dependent intracellular pH extrusion in freshly isolated CDs from TRPV4^-/- compared with WT mice fed a K⁺-deficient diet. Overall, our results demonstrate a novel kaliuretic role of TRPV4 by inhibiting H⁺-K⁺-ATPase-dependent K⁺ reabsorption in the CD. We propose that TRPV4 inhibition could be a novel strategy to manage certain hypokalemic states in clinical settings.