CHIP Regulates Aquaporin-2 Quality Control and Body Water Homeostasis.

Autor: Wu Q; InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark., Moeller HB; InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark., Stevens DA; McAllister Heart Institute and., Sanchez-Hodge R; McAllister Heart Institute and.; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Childers G; McAllister Heart Institute and.; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Kortenoeven MLA; InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark., Cheng L; InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark., Rosenbaek LL; InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Rubel C; McAllister Heart Institute and., Patterson C; Presbyterian Hospital/Weill-Cornell Medical Center, New York, New York; and., Pisitkun T; InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand., Schisler JC; McAllister Heart Institute and.; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Fenton RA; InterPrET Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark; robert.a.fenton@biomed.au.dk.
Jazyk: angličtina
Zdroj: Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2018 Mar; Vol. 29 (3), pp. 936-948. Date of Electronic Publication: 2017 Dec 14.
DOI: 10.1681/ASN.2017050526
Abstrakt: The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins have a regulatory role in these cells and how these cells can be regulated by individual physiologic stimuli. By combining proteomics, bioinformatics, and cell biology approaches, we found that the E3 ubiquitin ligase CHIP is highly expressed throughout the collecting duct; is modulated in abundance by vasopressin; interacts with aquaporin-2 (AQP2), Hsp70, and Hsc70; and can directly ubiquitylate the water channel AQP2 in vitro shRNA knockdown of CHIP in CCD cells increased AQP2 protein t 1/2 and reduced AQP2 ubiquitylation, resulting in greater levels of AQP2 and phosphorylated AQP2. CHIP knockdown increased the plasma membrane abundance of AQP2 in these cells. Compared with wild-type controls, CHIP knockout mice or novel CRISPR/Cas9 mice without CHIP E3 ligase activity had greater AQP2 abundance and altered renal water handling, with decreased water intake and urine volume, alongside higher urine osmolality. We did not observe significant changes in other water- or sodium-transporting proteins in the gene-modified mice. In summary, these results suggest that CHIP regulates AQP2 and subsequently, renal water handling.
(Copyright © 2018 by the American Society of Nephrology.)
Databáze: MEDLINE
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