title: Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH.
abstract: BACKGROUND
  Hypouricemia is pathognomonic in syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but the underlying mechanism remains unclear. Based on the previous studies, we hypothesized that V1a receptor may play a principal role in inducing hypouricemia in SIADH and examined uric acid metabolism using a rat model.
  
  
  METHODS
  Terlipressin (25 ng/h), a selective V1a agonist, was subcutaneously infused to 7-week-old male Wistar rats (n = 9). Control rats were infused with normal saline (n = 9). The rats were sacrificed to obtain kidney tissues 3 days after treatment. In addition to electrolyte metabolism, changes in expressions of the urate transporters including URAT1 (SLC22A12), GLUT9 (SLC2A9), ABCG2 and NPT1 (SLC17A1) were examined by western blotting and immunohistochemistry.
  
  
  RESULTS
  In the terlipressin-treated rats, serum uric acid (UA) significantly decreased and the excretion of urinary UA significantly increased, resulting in marked increase in fractional excretion of UA. Although no change in the expression of URAT1, GLUT9 expression significantly decreased whereas the expressions of ABCG2 and NPT1 significantly increased in the terlipressin group. The results of immunohistochemistry corroborated with those of the western blotting. Aquaporin 2 expression did not change in the medulla, suggesting the independence of V2 receptor stimulation.
  
  
  CONCLUSIONS
  Stimulation of V1a receptor induces the downregulation of GLUT9, reabsorption urate transporter, together with the upregulation of ABCG2 and NPT1, secretion urate transporters, all changes of which clearly lead to increase in renal UA clearance. Hypouricemia seen in SIADH is attributable to V1a receptor stimulation.
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
authors.forename: Yoshifuru
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.|Support for Community Medicine Endowed Chair, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kumagai
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan. s_uchida@netjoy.ne.jp.
authors.forename: Shunya
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000502:physiology; D000818:Animals; D051399:Aquaporin 2 / Q000032:analysis / Q000502:physiology; D007177:Inappropriate ADH Syndrome / Q000150:complications*; D008236:Lypressin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000502:physiology; D027361:Organic Anion Transporters / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000502:physiology*; D015499:Renal Tubular Transport, Inborn Errors / Q000209:etiology*; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000502:physiology; D000077585:Terlipressin; D014527:Uric Acid / Q000378:metabolism*; D014545:Urinary Calculi / Q000209:etiology*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C489249:Abcg2 protein, rat; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; C498776:GLUT6 protein, rat; D009004:Monosaccharide Transport Proteins; D027361:Organic Anion Transporters; D017483:Receptors, Vasopressin; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; C103862:urate transporter; D014527:Uric Acid; D008236:Lypressin; D000077585:Terlipressin
keywords: Aquaporin 2; Hypouricemia; SIADH; Terlipressin; Urate transporter; V1a receptor