Pflügers Archiv - European Journal of Physiology

, Volume 465, Issue 2, pp 233–245 | Cite as

Downregulation of the renal outer medullary K+ channel ROMK by the AMP-activated protein kinase

  • Balasaheb Siraskar
  • Dan Yang Huang
  • Tatsiana Pakladok
  • Gulab Siraskar
  • Mentor Sopjani
  • Ioana Alesutan
  • Yulia Kucherenko
  • Ahmad Almilaji
  • Vasudharani Devanathan
  • Ekaterina Shumilina
  • Michael Föller
  • Carlos Munoz
  • Florian Lang
Ion Channels, Receptors and Transporters

Abstract

The 5′-adenosine monophosphate-activated serine/threonine protein kinase (AMPK) is stimulated by energy depletion, increase in cytosolic Ca2+ activity, oxidative stress, and nitric oxide. AMPK participates in the regulation of the epithelial Na+ channel ENaC and the voltage-gated K+ channel KCNE1/KCNQ1. It is partially effective by decreasing PIP2 formation through the PI3K pathway. The present study explored whether AMPK regulates the renal outer medullary K+ channel ROMK. To this end, cRNA encoding ROMK was injected into Xenopus oocytes with and without additional injection of constitutively active AMPKγR70Q (AMPKα1-HA+AMPKβ1-Flag+AMPKγ1R70Q), or of inactive AMPKαK45R (AMPKα1K45R+AMPKβ1-Flag+AMPKγ1-HA), and the current determined utilizing two-electrode voltage-clamp and single channel patch clamp. ROMK protein abundance was measured utilizing chemiluminescence in Xenopus oocytes and western blot in whole kidney tissue. Moreover, renal Na+ and K+ excretion were determined in AMPKα1-deficient mice (ampk−/−) and wild-type mice (ampk+/+) prior to and following an acute K+ load (111 mM KCl, 30 mM NaHCO3, 4.7 mM NaCl, and 2.25 g/dl BSA) at a rate of 500 μl/h. As a result, coexpression of AMPKγR70Q but not of AMPKαK45R significantly decreased the current in ROMK1-expressing Xenopus oocytes. Injection of phosphatidylinositol PI(4,5)P2 significantly increased the current in ROMK1-expressing Xenopus oocytes, an effect reversed in the presence of AMPKγR70Q. Under control conditions, no significant differences between ampk−/− and ampk+/+ mice were observed in glomerular filtration rate (GFR), urinary flow rate, serum aldosterone, plasma Na+, and K+ concentrations as well as absolute and fractional Na+ and K+ excretion. Following an acute K+ load, GFR, urinary flow rate, serum aldosterone, plasma Na+, and K+ concentration were again similar in both genotypes, but renal absolute and fractional Na+ and K+ excretion were higher in ampk−/− than in ampk+/+ mice. According to micropuncture following a K+ load, delivery of Na+ to the early distal tubule but not delivery of K+ to late proximal and early distal tubules was increased in ampk−/− mice. The upregulation of renal ROMK1 protein expression by acute K+ load was more pronounced in ampk−/− than in ampk+/+ mice. In conclusion, AMPK downregulates ROMK, an effect compromising the ability of the kidney to excrete K+ following an acute K+ load.

Keywords

Energy depletion K+ channels ROMK Kaliuresis Natriuresis 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Balasaheb Siraskar
    • 1
  • Dan Yang Huang
    • 2
  • Tatsiana Pakladok
    • 1
  • Gulab Siraskar
    • 1
  • Mentor Sopjani
    • 1
    • 3
  • Ioana Alesutan
    • 1
  • Yulia Kucherenko
    • 1
  • Ahmad Almilaji
    • 1
  • Vasudharani Devanathan
    • 2
  • Ekaterina Shumilina
    • 1
  • Michael Föller
    • 1
    • 4
  • Carlos Munoz
    • 1
  • Florian Lang
    • 1
  1. 1.Department of PhysiologyUniversity of TübingenTübingenGermany
  2. 2.Department of Pharmacology and Experimental TherapyInstitute of Pharmacology and Toxicology, University of TübingenTübingenGermany
  3. 3.Faculty of MedicineUniversity of PrishtinaPrishtinaKosovo
  4. 4.Campbell Family Institute for Breast Cancer Research, Ontario Cancer InstituteUniversity Health Network (UHN)TorontoCanada

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