Pendrin-null mice develop severe hypokalemia following dietary Na+and K+restriction: role of ENaC

Truyen D. Pham, Anthony J. Elengickal, Jill W. Verlander, Lama Al-Qusairi, Chao Chen, Delaney C. Abood, Spencer A. King, Johannes Loffing, Paul A. Welling, Susan M. Wall

Research output: Contribution to journalArticlepeer-review

Abstract

Pendrin is an intercalated cell Cl-/HCO- 3 exchanger thought to participate in K+-sparing NaCl absorption. However, its role in K+homeostasis has not been clearly defined. We hypothesized that pendrin-null mice will develop hypokalemia with dietary K+restriction. We further hypothesized that pendrin knockout (KO) mice mitigate urinary K+loss by downregulating the epithelial Na+channel (ENaC). Thus, we examined the role of ENaC in Na+and K+balance in pendrin KO and wild-type mice following dietary K+restriction. To do so, we examined the relationship between Na+and K+balance and ENaC subunit abundance in K+-restricted pendrin-null and wild-type mice that were NaCl restricted or replete. Following a NaCl-replete, K+-restricted diet, K+balance and serum K+were similar in both groups. However, following a Na+, K+, and Cl-deficient diet, pendrin KO mice developed hypokalemia from increased K+excretion. The fall in serum K+observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. The fall in serum K+observed in K+-restricted pendrin KO mice was enhanced with ENaC stimulation but eliminated with ENaC inhibition. However, reducing ENaC activity also reduced blood pressure and increased apparent intravascular volume contraction, since KO mice had lower serum Na+, higher blood urea nitrogen and hemoglobin, greater weight loss, greater metabolic alkalosis, and greater NaCl excretion. We conclude that dietary Na+and K+restriction induces hypokalemia in pendrin KO mice. Pendrin-null mice limit renal K+loss by downregulating ENaC. However, this ENaC downregulation occurs at the expense of intravascular volume.

Original languageEnglish (US)
Pages (from-to)F486-F497
JournalAmerican Journal of Physiology - Renal Physiology
Volume322
Issue number5
DOIs
StatePublished - May 2022

Keywords

  • epithelial Nachannel; pendrin; potassium

ASJC Scopus subject areas

  • Urology
  • Physiology

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