title: Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase.
abstract: Statins are 3-hydroxyl-3-methyglutaryl-CoA reductase inhibitors that are commonly used to inhibit cholesterol biosynthesis. Emerging data have suggested that they also have "pleotropic effects," including modulating actin cytoskeleton reorganization. Here, we report an effect of simvastatin on the trafficking of aquaporin-2 (AQP2). Specifically, simvastatin induced the membrane accumulation of AQP2 in cell cultures and kidneys in situ. The effect of simvastatin was independent of protein kinase A activation and phosphorylation at AQP2-Ser(256), a critical event involved in vasopressin (VP)-regulated AQP2 trafficking. Further investigation showed that simvastatin inhibited endocytosis in parallel with downregulation of RhoA activity. Overexpression of active RhoA attenuated simvastatin's effect, suggesting the involvement of this small GTPase in simvastatin-mediated AQP2 trafficking. Finally, the effect of simvastatin on urinary concentration was investigated in VP-deficient Brattleboro rats. Simvastatin acutely (3-6 h) increased urinary concentration and decreased urine output in these animals. In summary, simvastatin regulates AQP2 trafficking in vitro and urinary concentration in vivo via events involving downregulation of Rho GTPase activity and inhibition of endocytosis. Our study provides an alternative mechanism to regulate AQP2 trafficking, bypassing the VP-vasopressin receptor signaling pathway.
authors.affiliation: Center for Systems Biology, Program in Membrane Biology, Division of Nephrology, Dept. of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Bouley
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsuzaki
authors.forename: Paula
authors.initials: P
authors.lastname: Nunes
authors.forename: Udo
authors.initials: U
authors.lastname: Hasler
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.forename: Hua A Jenny
authors.initials: HA
authors.lastname: Lu
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000652:urine*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011910:Rats, Brattleboro; D019821:Simvastatin / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020741:rho GTP-Binding Proteins