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

  • Ion Channels, Receptors and Transporters
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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.

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Acknowledgments

The authors gratefully acknowledge the generosity of Benoit Viollet, Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (UMR8104), Paris, France; INSERM, U1016, Paris, France, for providing the ampk −/− mice. The authors further acknowledge the technical assistance of E. Faber. The manuscript was meticulously prepared by S. Rübe. This study was supported by the Deutsche Forschungsgemeinschaft (DFG HU 1600/1-2) and the IZKF of the University of Tübingen (Nachwuchsgruppe to M.F.).

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Authors and Affiliations

  1. Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany

    Balasaheb Siraskar, Tatsiana Pakladok, Gulab Siraskar, Mentor Sopjani, Ioana Alesutan, Yulia Kucherenko, Ahmad Almilaji, Ekaterina Shumilina, Michael Föller, Carlos Munoz & Florian Lang

  2. Department of Pharmacology and Experimental Therapy, Institute of Pharmacology and Toxicology, University of Tübingen, Wilhelmstr. 56, 72074, Tübingen, Germany

    Dan Yang Huang & Vasudharani Devanathan

  3. Faculty of Medicine, University of Prishtina, Str. Bulevardi i Dëshmorëve, p.n., 10000, Prishtina, Kosovo

    Mentor Sopjani

  4. Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network (UHN), Toronto, Ontario, M5G 2C1, Canada

    Michael Föller

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  1. Balasaheb Siraskar
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  2. Dan Yang Huang
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Correspondence to Florian Lang.

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Balasaheb Siraskar and Dan Yang Huang contributed equally to this work and thus share first authorship.

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Siraskar, B., Huang, D.Y., Pakladok, T. et al. Downregulation of the renal outer medullary K+ channel ROMK by the AMP-activated protein kinase. Pflugers Arch - Eur J Physiol 465, 233–245 (2013). https://doi.org/10.1007/s00424-012-1180-1

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