TRPV4 expression in the renal tubule is necessary for maintaining whole body K homeostasis.

The Ca-permeable transient receptor potential vanilloid type 4 (TRPV4) channel serves as the sensor of tubular flow, thus being well suited to govern mechanosensitive K transport in the distal renal tubule. Here, we directly tested whether the TRPV4 function is significant in affecting K balance. We used balance metabolic cage experiments and systemic measurements with different K feeding regimens [high (5% K), regular (0.9% K), and low (<0.01% K)] in newly created transgenic mice with selective TRPV4 deletion in the renal tubule (TRPV4-Pax8Cre) and their littermate controls (TRPV4). Deletion was verified by the absence of TRPV4 protein expression and lack of TRPV4-dependent Ca influx. There were no differences in plasma electrolytes, urinary volume, and K levels at baseline. In contrast, plasma K levels were significantly elevated in TRPV4-Pax8Cre mice on high K intake. K-loaded knockout mice exhibited lower urinary K levels than TRPV4 mice, which was accompanied by higher aldosterone levels by . Moreover, TRPV4-Pax8Cre mice had more efficient renal K conservation and higher plasma K levels in the state of dietary K deficiency. H-K-ATPase levels were significantly increased in TRPV4-Pax8Cre mice on a regular diet and especially on a low-K diet, pointing to augmented K reabsorption in the collecting duct. Consistently, we found a significantly faster intracellular pH recovery after intracellular acidification, as an index of H-K-ATPase activity, in split-opened collecting ducts from TRPV4-Pax8Cre mice. In summary, our results demonstrate an indispensable prokaliuretic role of TRPV4 in the renal tubule in controlling K balance and urinary K excretion during variations in dietary K intake. The mechanoactivated transient receptor potential vanilloid type 4 (TRPV4) channel is expressed in distal tubule segments, where it controls flow-dependent K transport. Global TRPV4 deficiency causes impaired adaptation to variations in dietary K intake. Here, we demonstrate that renal tubule-specific TRPV4 deletion is sufficient to recapitulate the phenotype by causing antikaliuresis and higher plasma K levels in both states of K load and deficiency.