CHIP regulates aquaporin-2 quality control and body water homeostasis

Qi Wu, Hanne B. Møller, Donté A. Stevens, Rebekah Sanchez-Hodge, Gabrielle Childers, Marleen L.A. Kortenoeven, Lei Cheng, Lean L. Rosenbaek, Carrie Rubel, Cam Patterson, Trairak Pisitkun, Jonathan C. Schisler, Robert A. Fenton*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 andphosphorylatedAQP2.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 CHIPE3 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.

OriginalsprogEngelsk
TidsskriftJournal of the American Society of Nephrology
Vol/bind29
Udgave nummer3
Sider (fra-til)936-948
ISSN1046-6673
DOI
StatusUdgivet - mar. 2018
Udgivet eksterntJa

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