Arginase‐II negatively regulates renal aquaporin‐2 and water reabsorption

• Published in: The FASEB journal Vol. 32; no. 10; pp. 5520 - 5531
• Main Authors: Huang, Ji, Montani, Jean‐Pierre, Verrey, François, Feraille, Eric, Ming, Xiu‐Fen, Yang, Zhihong
• Format: Journal Article
• Language: English
• Published: United States Federation of American Societies for Experimental Biology 01.10.2018
• Subjects: collecting duct; copeptin; osmolality; urine; vasopressin; copeptin; osmolality; collecting duct; urine; vasopressin
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201701209R

ABSTRACT Type‐II L‐arginine:ureahydrolase, arginase‐II (Arg‐II), is abundantly expressed in the kidney. The physiologic role played by Arg‐II in the kidney remains unknown. Herein, we report that in mice that are deficient in Arg‐II (Arg‐II−/−), total and membrane‐associated aquaporin‐2 (AQP2) protein levels were significantly higher compared with wild‐type (WT) controls. Water deprivation enhanced Arg‐II expression, AQP2 levels, and membrane association in collecting ducts. Effects of water deprivation on AQP2 were stronger in Arg‐II−/− mice than in WT mice. Accordingly, a decrease in urine volume and an increase in urine osmolality under water deprivation were more pronounced in Arg‐II_/_ mice than in WT mice, which correlated with a weaker increase in plasma osmolality in Arg‐II_/_ mice. There was no difference in vasopressin release under water deprivation conditions between either genotype of mice. Although total AQP2 and phosphorylated AQP2‐S256 levels (mediated by PKA) in kidneys under water deprivation conditions were significantly higher in Arg‐II_/_ mice compared with WT animals, there is no difference in the ratio of AQP2‐S256:AQP2. In cultured mouse collecting duct principal mCCDcl1 cells, expression of both Arg‐II and AQP2 were enhanced by the vasopressin type 2 receptor agonist, desamino‐d‐arginine vasopressin (dDAVP). Silencing Arg‐II enhanced the expression and membrane association of AQP2 by dDAVP without influencing cAMP levels. In conclusion, in vivo and in vitro experiments demonstrate that Arg‐II negatively regulates AQP2 and the urine‐ concentrating capability in kidneys via a mechanism that is not associated with the modulation of the cAMP pathway.—Huang, J., Montani, J.‐P., Verrey, F., Feraille, E., Ming, X.‐F., Yang, Z. Arginase‐II negatively regulates renal aquaporin‐2 and water reabsorption. FASEB J. 32, 5520–5531 (2018). www.fasebj.org