title: Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice.
abstract: X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI.
authors: 1] Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy [2] Centro di Eccellenza di Genomica in Campo Biomedico ed Agrario (CEGBA), Bari, Italy.
authors: Giuseppe
authors: G
authors: Procino
authors: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors: Serena
authors: S
authors: Milano
authors: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors: Monica
authors: M
authors: Carmosino
authors: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors: Claudia
authors: C
authors: Barbieri
authors: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
authors: Maria C
authors: MC
authors: Nicoletti
authors: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
authors: Jian H
authors: JH
authors: Li
authors: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
authors: Jürgen
authors: J
authors: Wess
authors: 1] Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy [2] Centro di Eccellenza di Genomica in Campo Biomedico ed Agrario (CEGBA), Bari, Italy.
authors: Maria
authors: M
authors: Svelto
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D018500:Diabetes Insipidus, Nephrogenic / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005089:Exocytosis; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage*; D000077340:Fluvastatin; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011141:Polyuria / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000172:deficiency / Q000235:genetics; D012633:Secretin / Q000008:administration & dosage*
chemical_list: C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D017483:Receptors, Vasopressin; C029937:secretin receptor; D012633:Secretin; D000077340:Fluvastatin; D000242:Cyclic AMP