title: Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts.
abstract: Nephrogenic diabetes insipidus (NDI) is characterized by production of very large quantities of dilute urine due to an inability of the kidney to respond to vasopressin. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in ∼90% of families. These patients do not have mutations in aquaporin-2 (AQP2) or urea transporter UT-A1 (UT-A1). We tested adenosine monophosphate kinase (AMPK) since it is known to phosphorylate another vasopressin-sensitive transporter, NKCC2 (Na-K-2Cl cotransporter). We found AMPK expressed in rat inner medulla (IM). AMPK directly phosphorylated AQP2 and UT-A1 in vitro. Metformin, an AMPK activator, increased phosphorylation of both AQP2 and UT-A1 in rat inner medullary collecting ducts (IMCDs). Metformin increased the apical plasma membrane accumulation of AQP2, but not UT-A1, in rat IM. Metformin increased both osmotic water permeability and urea permeability in perfused rat terminal IMCDs. These findings suggest that metformin increases osmotic water permeability by increasing AQP2 accumulation in the apical plasma membrane but increases urea permeability by activating UT-A1 already present in the membrane. Lastly, metformin increased urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. We conclude that AMPK activation by metformin mimics many of the mechanisms by which vasopressin increases urine-concentrating ability. These findings suggest that metformin may be a novel therapeutic option for congenital NDI due to V2R mutations.
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia; and Department of Physiology, Emory University, Atlanta, Georgia janet.klein@emory.edu.
authors.forename: Janet D
authors.identifier: 0000-0001-6663-1129
authors.initials: JD
authors.lastname: Klein
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia; and Department of Physiology, Emory University, Atlanta, Georgia.
authors.forename: Mitsi A
authors.initials: MA
authors.lastname: Blount
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Molina
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: LaRocque
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia; and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ruiz
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, Georgia; and Department of Physiology, Emory University, Atlanta, Georgia.
authors.forename: Jeff M
authors.identifier: 0000-0001-9822-0607
authors.initials: JM
authors.lastname: Sands
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism*; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy* / Q000652:urine; D004353:Drug Evaluation, Preclinical; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000378:metabolism; D014867:Water / Q000378:metabolism; D000096982:Urea Transporters
chemical_list: D055372:AMP-Activated Protein Kinases; D051399:Aquaporin 2; D007004:Hypoglycemic Agents; D026901:Membrane Transport Proteins; D008687:Metformin; D014508:Urea; D014867:Water; D000096982:Urea Transporters; C496025:Aqp2 protein, rat
keywords: AMPK; diabetes insipidus; kinases; urine concentration; vasopressin