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

Abstract

Distal segments of the renal tubule have a major role in controlling whole body K + homeostasis by performing flow-induced K + secretion (FIKS) during K + load and K+ reabsorption in response to systemic K + deficiency. The transient receptor potential vanilloid type 4 (TRPV4) Ca2 + -permeable channel serves as the sensor of tubular flow thus being well-suited to govern K + transport in the distal renal tubule. In the current manuscript, we directly tested whether TRPV4 function in the renal tubule is significant in affecting K + balance. For this, we employed balance metabolic cage studies 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 (TRPV4fl/fl-Pax8Cre) and their littermate genetic controls (TRPV4fl/fl). Successful deletion was verified by the absence of TRPV4 protein expression in renal homogenates and the lack of TRPV4-mediated Ca2 + influx in freshly-isolated split-opened collecting ducts. There were no differences in plasma electrolytes, baseline urinary volume, and K + levels when both strains were fed regular K + intake. In contrast, plasma K+ levels were significantly elevated in TRPV4fl/fl-Pax8Cre mice on both high and low K + intake. This was associated with a marked decrease in 24 h urinary K+ levels in the knockout, whereas urinary volume and aldosterone levels were indistinguishable from the control TRPV4fl/fl littermates suggesting a direct decrease in the distal tubule K + transport. Interestingly, we also detected significant differences in urinary pH levels indicative of the altered K + reabsorption via H + -K + ATPase in the collecting duct. Indeed, we detected a significantly faster pHi recovery after intracellular acidification with ammonium pulse in both acid secreting A- and base-secreting B-types of intercalated cells and to a lesser degree in principal cells in split-opened collecting ducts from TRPV4fl/fl-Pax8Cre mice on low but not regular K + intake, which is consistent with augmented H + -K + ATPase activity and K + reabsorption in the knockouts. In summary, our results demonstrate an indispensable pro-kaliuretic role of TRPV4 in the renal tubule in controlling K + balance and urinary K + excretion during variations in dietary K + intake This research was supported by NIH-NIDDK DK117865, DK119170, AHA EIA35260097 (to O. Pochynyuk) and AHA-19CDA34660148 (to V. N. Tomilin). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.