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

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  • Marleen L A Kortenoeven, Department of Cardiovascular and Renal Research, Syddansk Universitet Institut for Molekylar Medicin, Odense, Denmark., Institute for Molecular Medicine, University of Southern Denmark
  • ,
  • Cristina Esteva-Font, Department of Biomedicine - Pharmacology
  • ,
  • Henrik Dimke, Department of Cardiovascular and Renal Research, Syddansk Universitet Institut for Molekylar Medicin, Odense, Denmark., Institute for Molecular Medicine, University of Southern Denmark, Odense University Hospital, Odense, Denmark.
  • ,
  • Søren B Poulsen
  • Sathish K Murali
  • ,
  • Robert A Fenton

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.

Original languageEnglish
JournalThe Journal of Biological Chemistry
Volume297
Issue2
Pages (from-to)100915
ISSN0021-9258
DOIs
Publication statusE-pub ahead of print - 24 Jun 2021

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Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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