Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla.
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Kortenoeven ML, Sinke AP, Hadrup N, Trimpert C, Wetzels JF, Fenton RA, Deen PM
Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla.
Am J Physiol Renal Physiol. 2013 Dec 15;305(12):F1705-18. doi: 10.1152/ajprenal.00723.2012. Epub 2013 Oct 23.
- PubMed ID
- 24154696 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Demeclocycline Vasopressin V2 receptor Protein Humans UnknownInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareDesmopressinDemeclocycline The therapeutic efficacy of Desmopressin can be decreased when used in combination with Demeclocycline.