Essential role of Kir5.1 channels in renal salt handling and blood pressure control

JCI Insight. 2017 Sep 21;2(18):e92331. doi: 10.1172/jci.insight.92331.

Abstract

Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels Kir4.1 (Kcnj10) and Kir5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na+ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of Kir5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SSKcnj16-/-). SSKcnj16-/- rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia. Electrophysiological recordings of basolateral K+ channels in the collecting ducts isolated from SSKcnj16-/- rats revealed activity of only homomeric Kir4.1 channels. Kir4.1 expression was upregulated in SSKcnj16-/- rats, but the protein was predominantly localized in the cytosol in SSKcnj16-/- rats. Benzamil, but not hydrochlorothiazide or furosemide, rescued this phenotype from mortality on a high-salt diet. Supplementation of high-salt diet with increased potassium (2% KCl) prevented mortality in SSKcnj16-/- rats and prevented or mitigated hypertension in SSKcnj16-/- or control SS rats, respectively. Our results demonstrate that Kir5.1 channels are key regulators of renal salt handling in SS hypertension.

Keywords: Epithelial transport of ions and water; Ion channels; Nephrology; Potassium channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amiloride / analogs & derivatives
  • Amiloride / pharmacology
  • Animals
  • Blood Pressure / physiology*
  • Female
  • Furosemide / pharmacology
  • Hydrochlorothiazide / pharmacology
  • Kidney Tubules, Distal / metabolism*
  • Male
  • Mutation
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / physiology*
  • Rats
  • Rats, Inbred Dahl
  • Sodium Chloride / metabolism*
  • Sodium Chloride, Dietary / administration & dosage

Substances

  • Kir5.1 channel
  • Potassium Channels, Inwardly Rectifying
  • Sodium Chloride, Dietary
  • benzamil
  • Hydrochlorothiazide
  • Sodium Chloride
  • Amiloride
  • Furosemide