Anna Stavniichuk, Kyrylo Pyrshev, Oleg Zaika, Viktor N Tomilin, Mariya Kordysh, Monika Lakk, David Križaj, Oleh Pochynyuk
{"title":"TRPV4 expression in the renal tubule is necessary for maintaining whole body K<sup>+</sup> homeostasis.","authors":"Anna Stavniichuk, Kyrylo Pyrshev, Oleg Zaika, Viktor N Tomilin, Mariya Kordysh, Monika Lakk, David Križaj, Oleh Pochynyuk","doi":"10.1152/ajprenal.00278.2022","DOIUrl":null,"url":null,"abstract":"<p><p>The Ca<sup>2+</sup>-permeable transient receptor potential vanilloid type 4 (TRPV4) channel serves as the sensor of tubular flow, thus being well suited to govern mechanosensitive K<sup>+</sup> transport in the distal renal tubule. Here, we directly tested whether the TRPV4 function is significant in affecting K<sup>+</sup> balance. We used balance metabolic cage experiments and systemic measurements with different K<sup>+</sup> feeding regimens [high (5% K<sup>+</sup>), regular (0.9% K<sup>+</sup>), and low (<0.01% K<sup>+</sup>)] in newly created transgenic mice with selective TRPV4 deletion in the renal tubule (TRPV4<sup>fl/fl</sup>-Pax8Cre) and their littermate controls (TRPV4<sup>fl/fl</sup>). Deletion was verified by the absence of TRPV4 protein expression and lack of TRPV4-dependent Ca<sup>2+</sup> influx. There were no differences in plasma electrolytes, urinary volume, and K<sup>+</sup> levels at baseline. In contrast, plasma K<sup>+</sup> levels were significantly elevated in TRPV4<sup>fl/fl</sup>-Pax8Cre mice on high K<sup>+</sup> intake. K<sup>+</sup>-loaded knockout mice exhibited lower urinary K<sup>+</sup> levels than TRPV4<sup>fl/fl</sup> mice, which was accompanied by higher aldosterone levels by <i>day 7</i>. Moreover, TRPV4<sup>fl/fl</sup>-Pax8Cre mice had more efficient renal K<sup>+</sup> conservation and higher plasma K<sup>+</sup> levels in the state of dietary K<sup>+</sup> deficiency. H<sup>+</sup>-K<sup>+</sup>-ATPase levels were significantly increased in TRPV4<sup>fl/fl</sup>-Pax8Cre mice on a regular diet and especially on a low-K<sup>+</sup> diet, pointing to augmented K<sup>+</sup> reabsorption in the collecting duct. Consistently, we found a significantly faster intracellular pH recovery after intracellular acidification, as an index of H<sup>+</sup>-K<sup>+</sup>-ATPase activity, in split-opened collecting ducts from TRPV4<sup>fl/fl</sup>-Pax8Cre mice. In summary, our results demonstrate an indispensable prokaliuretic role of TRPV4 in the renal tubule in controlling K<sup>+</sup> balance and urinary K<sup>+</sup> excretion during variations in dietary K<sup>+</sup> intake. <b>NEW & NOTEWORTHY</b> The mechanoactivated transient receptor potential vanilloid type 4 (TRPV4) channel is expressed in distal tubule segments, where it controls flow-dependent K<sup>+</sup> transport. Global TRPV4 deficiency causes impaired adaptation to variations in dietary K<sup>+</sup> intake. Here, we demonstrate that renal tubule-specific TRPV4 deletion is sufficient to recapitulate the phenotype by causing antikaliuresis and higher plasma K<sup>+</sup> levels in both states of K<sup>+</sup> load and deficiency.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":"324 6","pages":"F603-F616"},"PeriodicalIF":3.7000,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10281785/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Physiology-renal Physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajprenal.00278.2022","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/5/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
引用次数: 0
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 (TRPV4fl/fl-Pax8Cre) and their littermate controls (TRPV4fl/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 TRPV4fl/fl-Pax8Cre mice on high K+ intake. K+-loaded knockout mice exhibited lower urinary K+ levels than TRPV4fl/fl mice, which was accompanied by higher aldosterone levels by day 7. Moreover, TRPV4fl/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 TRPV4fl/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 TRPV4fl/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.
期刊介绍:
The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.