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Author Notes:

Address correspondence to: Jeff M. Sands, Emory University School of Medicine, Renal Division, 101 Woodruff Circle, WMB 338, Atlanta, Georgia 30322 USA. Phone: 404.727.2525; Email: jeff.sands@emory.edu

OE planned and executed experiments, collected and analyzed data, and wrote the manuscript.

JDK planned experiments, prepared samples, analyzed data, and edited the manuscript.

LML prepared samples and collected data.

HR prepared samples and collected data.

JMS planned the project, analyzed data, and edited the manuscript.

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

This work was supported by NIH grant R01-DK41707 and by an Otsuka Investigator-Sponsored Study (20135297).

Tolvaptan was a gift from Otsuka.

The V2R KO mice were a gift from Jurgen Wess, NIH.

Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus.

Tools:

Journal Title:

JCI insight

Volume:

Volume 1, Number 11

Publisher:

, Pages e88409-e88409

Type of Work:

Article | Final Publisher PDF

Abstract:

Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/ kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 ± 126 mOsM) was restored to control levels by metformin (2,335 ± 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na(+)-K(+)-2Cl(-) cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R-blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI.

Copyright information:

© 2016, American Society for Clinical Investigation

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