title: Fluvastatin modulates renal water reabsorption in vivo through increased AQP2 availability at the apical plasma membrane of collecting duct cells.
abstract: X-linked nephrogenic diabetes insipidus (XNDI), a severe pathological condition characterized by greatly impaired urine-concentrating ability of the kidney, is caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene. The lack of functional V2Rs prevents vasopressin-induced shuttling of aquaporin-2 (AQP2) water channels to the apical plasma membrane of kidney collecting duct principal cells, thus promoting water reabsorption from urine to the interstitium. At present, no specific pharmacological therapy exists for the treatment of XNDI. We have previously reported that the cholesterol-lowering drug lovastatin increases AQP2 membrane expression in renal cells in vitro. Here we report the novel finding that fluvastatin, another member of the statins family, greatly increases kidney water reabsorption in vivo in mice in a vasopressin-independent fashion. Consistent with this observation, fluvastatin is able to increase AQP2 membrane expression in the collecting duct of treated mice. Additional in vivo and in vitro experiments indicate that these effects of fluvastatin are most likely caused by fluvastatin-dependent changes in the prenylation status of key proteins regulating AQP2 trafficking in collecting duct cells. We identified members of the Rho and Rab families of proteins as possible candidates whose reduced prenylation might result in the accumulation of AQP2 at the plasma membrane. In conclusion, these results strongly suggest that fluvastatin, or other drugs of the statin family, may prove useful in the therapy of XNDI.
authors.affiliation: Department of General and Environmental Physiology, University of Bari, Bari, Italy. g.procino@biologia.uniba.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Procino
authors.forename: Claudia
authors.initials: C
authors.lastname: Barbieri
authors.forename: Monica
authors.initials: M
authors.lastname: Carmosino
authors.forename: Grazia
authors.initials: G
authors.lastname: Tamma
authors.forename: Serena
authors.initials: S
authors.lastname: Milano
authors.forename: Leonarda
authors.initials: L
authors.lastname: De Benedictis
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Mola
authors.forename: Yoskaly
authors.initials: Y
authors.lastname: Lazo-Fernandez
authors.forename: Giovanna
authors.initials: G
authors.lastname: Valenti
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000096:biosynthesis / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000627:therapeutic use; D000077340:Fluvastatin; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054876:Prenylation / Q000187:drug effects; D020691:rab GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D054460:rho-Associated Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D051399:Aquaporin 2; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D054460:rho-Associated Kinases; D020691:rab GTP-Binding Proteins