TRPV4 inhibition protects against hypokalemia during low K+ intake

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. Distal renal tubule and specifically the collecting duct (CD) is the only place of controlled K+ reabsorption via H+‐K+‐ATPase in the state of dietary K+ deficiency. We previously demonstrated that TRPV4 Ca2+ channel, abundantly expressed in the CD, is a potent kaliuretic factor essential for 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 low K+ diet (<0.01% K+) for 7 days reduced plasma K+ levels in WT mice from 4.3±0.2 mM to 3.3±0.2 mM, but not in TRPV4 −/− mice (4.3±0.1 mM and 4.2±0.3 mM, respectively). Furthermore, we detected significant reduction in urinary K+ levels in balance studies upon switching to low K+ diet in the presence of TRPV4 inhibition. By using freshly isolated split‐opened CDs, we detected greatly accelerated H+‐K+‐ATPase‐dependent pHi extrusion in TRPV4 −/− mice when compared to WT mice. Finally, TRPV4 −/− animals had significantly more acidic urine (6.2±0.1 vs 6.7±0.2 in WT) on low K+ diet, which is consistent with increased H+‐K+ ATPase activity. In summary, we propose that TRPV4 inhibition could be a novel strategy to manage certain hypokalemic states in clinical setting. Support or Funding Information This research was supported by NIH‐NIDDK DK095029 (to O. P.), AHA 17GRNT33660488 (to O. P.), and ASN Ben J. Lipps Research Fellowship (to V. T.). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .