IGF-1 and insulin exert opposite actions on ClC-K2 activity in the cortical collecting ducts

Oleg Zaika, Mykola Mamenko, Nabila Boukelmoune, Oleh Pochynyuk

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Despite similar stimulatory actions on the epithelial sodium channel (ENaC)-mediated sodium reabsorption in the distal tubule, insulin promotes kaliuresis, whereas insulin-like growth factor-1 (IGF-1) causes a reduction in urinary potassium levels. The factors contributing to this phenomenon remain elusive. Electrogenic distal nephron ENaC-mediated Na+ transport establishes driving force for Cl- reabsorption and K+ secretion. Using patch-clamp electrophysiology, we document that a Cl- channel is highly abundant on the basolateral plasma membrane of intercalated cells in freshly isolated mouse cortical collecting duct (CCD) cells. The channel has characteristics attributable to the ClC-K2: slow gating kinetics, conductance ∼10 pS, voltage independence, Cl->NO-3 anion selectivity, and inhibition/ activation by low/high pH, respectively. IGF-1 (100 and 500 nM) acutely stimulates ClC-K2 activity in a reversible manner. Inhibition of PI3-kinase (PI3-K) with LY294002 (20 μM) abrogates activation of ClC-K2 by IGF-1. Interestingly, insulin (100 nM) reversibly decreases ClC-K2 activity in CCD cells. This inhibitory action is independent of PI3-K and is mediated by stimulation of a mitogenactivated protein kinase-dependent cascade. We propose that IGF-1, by stimulating ClC-K2 channels, promotes net Na+ and Cl- reabsorption, thus reducing driving force for potassium secretion by the CCD. In contrast, inhibition of ClC-K2 by insulin favors coupling of Na+ reabsorption with K+ secretion at the apical membrane contributing to kaliuresis.

Original languageEnglish (US)
Pages (from-to)F39-F48
JournalAmerican Journal of Physiology - Renal Physiology
Volume308
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Cl reabsorption
  • Distal nephron
  • Epithelial transport
  • Urinary K excretion

ASJC Scopus subject areas

  • Physiology
  • Urology

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