title: Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus.
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.
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Orhan
authors.initials: O
authors.lastname: Efe
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.|Department of Physiology, Emory University, Atlanta, Georgia, USA.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: LaRocque
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Ren
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.|Department of Physiology, Emory University, Atlanta, Georgia, USA.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Sands