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

Abstract

The Ca²⁺-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^fl/fl-Pax8Cre) and their littermate controls (TRPV4^fl/fl). Deletion was verified by the absence of TRPV4 protein expression and lack of TRPV4-dependent Ca²⁺ 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^fl/fl-Pax8Cre mice on high K⁺ intake. K⁺-loaded knockout mice exhibited lower urinary K⁺ levels than TRPV4^fl/fl mice, which was accompanied by higher aldosterone levels by day 7. Moreover, TRPV4^fl/fl-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^fl/fl-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^fl/fl-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. NEW & NOTEWORTHY 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.

Keywords: distal tubule K+ transport; flow sensitivity; hyperkalemia; hypokalemia; kaliuresis.