Deletion of Kir5.1 Impairs Renal Ability to Excrete Potassium during Increased Dietary Potassium Intake

J Am Soc Nephrol. 2019 Aug;30(8):1425-1438. doi: 10.1681/ASN.2019010025. Epub 2019 Jun 25.

Abstract

Background: The basolateral potassium channel in the distal convoluted tubule (DCT), comprising the inwardly rectifying potassium channel Kir4.1/Kir5.1 heterotetramer, plays a key role in mediating the effect of dietary potassium intake on the thiazide-sensitive NaCl cotransporter (NCC). The role of Kir5.1 (encoded by Kcnj16) in mediating effects of dietary potassium intake on the NCC and renal potassium excretion is unknown.

Methods: We used electrophysiology, renal clearance, and immunoblotting to study Kir4.1 in the DCT and NCC in Kir5.1 knockout (Kcnj16-/- ) and wild-type (Kcnj16+/+ ) mice fed with normal, high, or low potassium diets.

Results: We detected a 40-pS and 20-pS potassium channel in the basolateral membrane of the DCT in wild-type and knockout mice, respectively. Compared with wild-type, Kcnj16-/- mice fed a normal potassium diet had higher basolateral potassium conductance, a more negative DCT membrane potential, higher expression of phosphorylated NCC (pNCC) and total NCC (tNCC), and augmented thiazide-induced natriuresis. Neither high- nor low-potassium diets affected the basolateral DCT's potassium conductance and membrane potential in Kcnj16-/- mice. Although high potassium reduced and low potassium increased the expression of pNCC and tNCC in wild-type mice, these effects were absent in Kcnj16-/- mice. High potassium intake inhibited and low intake augmented thiazide-induced natriuresis in wild-type but not in Kcnj16-/- mice. Compared with wild-type, Kcnj16-/- mice with normal potassium intake had slightly lower plasma potassium but were more hyperkalemic with prolonged high potassium intake and more hypokalemic during potassium restriction.

Conclusions: Kir5.1 is essential for dietary potassium's effect on NCC and for maintaining potassium homeostasis.

Keywords: distal tubule; electrophysiology; hypokalemia; potassium channels.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Diet
  • Female
  • Gene Deletion*
  • Homeostasis
  • Hyperkalemia / metabolism
  • Hypokalemia / metabolism
  • Kidney / metabolism*
  • Kidney Tubules, Distal / metabolism
  • Kir5.1 Channel
  • Male
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / physiology*
  • Potassium, Dietary / pharmacokinetics*
  • Solute Carrier Family 12, Member 3 / metabolism
  • Thiazides / chemistry

Substances

  • Kcnj10 (channel)
  • Kcnj16 protein, mouse
  • Potassium Channels, Inwardly Rectifying
  • Potassium, Dietary
  • Solute Carrier Family 12, Member 3
  • Thiazides