Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus.

• Authors: Orhan Efe, Emory University; Janet Klein, Emory University; Lauren M. LaRocque, Emory University; Huiwen Ren, Emory University; Jeff Sands, Emory University
• Journal Title: JCI insight
• Volume: Volume 1, Number 11
• Publisher: American Society for Clinical Investigation | 2016-07-21, Pages e88409-e88409
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/jci.insight.88409
• Subjects: Biology, Physiology; Health Sciences, Immunology

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.