High dietary potassium causes ubiquitin-dependent degradation of the kidney sodium-chloride cotransporter.

Autor:	Kortenoeven MLA; Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. Electronic address: kortenoeven@health.sdu.dk., Esteva-Font C; Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark., Dimke H; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Nephrology, Odense University Hospital, Odense, Denmark., Poulsen SB; Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark., Murali SK; Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark., Fenton RA; Department of Biomedicine, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark. Electronic address: Robert.a.fenton@biomed.au.dk.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Aug; Vol. 297 (2), pp. 100915. Date of Electronic Publication: 2021 Jun 24.
DOI:	10.1016/j.jbc.2021.100915
Abstrakt:	The thiazide-sensitive sodium-chloride cotransporter (NCC) in the renal distal convoluted tubule (DCT) plays a critical role in regulating blood pressure (BP) and K + homeostasis. During hyperkalemia, reduced NCC phosphorylation and total NCC abundance facilitate downstream electrogenic K + secretion and BP reduction. However, the mechanism for the K + -dependent reduction in total NCC levels is unknown. Here, we show that NCC levels were reduced in ex vivo renal tubules incubated in a high-K + medium for 24-48 h. This reduction was independent of NCC transcription, but was prevented using inhibitors of the proteasome (MG132) or lysosome (chloroquine). Ex vivo, high K + increased NCC ubiquitylation, but inhibition of the ubiquitin conjugation pathway prevented the high K + -mediated reduction in NCC protein. In tubules incubated in high K + media ex vivo or in the renal cortex of mice fed a high K + diet for 4 days, the abundance and phosphorylation of heat shock protein 70 (Hsp70), a key regulator of ubiquitin-dependent protein degradation and protein folding, were decreased. Conversely, in similar samples the expression of PP1α, known to dephosphorylate Hsp70, was also increased. NCC coimmunoprecipitated with Hsp70 and PP1α, and inhibiting their actions prevented the high K + -mediated reduction in total NCC levels. In conclusion, we show that hyperkalemia drives NCC ubiquitylation and degradation via a PP1α-dependent process facilitated by Hsp70. This mechanism facilitates K + -dependent reductions in NCC to protect plasma K + homeostasis and potentially reduces BP. Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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