TRPV4 deletion protects against hypokalemia during systemic K+ deficiency

Viktor Tomilin, Mykola Mamenko, Oleg Zaika, Charles S. Wingo, Oleh Pochynyuk

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)F948-F956
JournalAmerican Journal of Physiology - Renal Physiology
Volume316
Issue number5
DOIs
Publication statusPublished - May 2019

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Keywords

  • Collecting duct
  • Intercalated cells
  • Intracellular pH
  • K transport
  • Principal cells

ASJC Scopus subject areas

  • Physiology
  • Urology

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