title: Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla.
abstract: Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-D-arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments.
authors.affiliation: no. 286, Dept. of Physiology, Radboud Univ. Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands. p.deen@fysiol.umcn.nl.
authors.forename: Marleen L A
authors.initials: ML
authors.lastname: Kortenoeven
authors.forename: Anne P
authors.initials: AP
authors.lastname: Sinke
authors.forename: Niels
authors.initials: N
authors.lastname: Hadrup
authors.forename: Christiane
authors.initials: C
authors.lastname: Trimpert
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D051399:Aquaporin 2 / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000009:adverse effects; D003707:Demeclocycline / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007010:Hyponatremia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D066298:In Vitro Techniques; D007177:Inappropriate ADH Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014667:Vasopressins / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D051399:Aquaporin 2; D014667:Vasopressins; D003707:Demeclocycline; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V; D003894:Deamino Arginine Vasopressin; D008911:Minocycline
keywords: aquaporin 2; collecting duct; demeclocycline; syndrome of inappropriate antidiuretic hormone secretion; vasopressin