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Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

Virginie Bernier^*, Jean-Pierre Morello^*, Alexandro Zarruk, Nicolas Debrand, Ali Salahpour^*, Michèle Lonergan, Marie-Françoise Arthus, André Laperrière^*, Rémi Brouard, Michel Bouvier^* and Daniel G. Bichet^,

^* Department of Biochemistry, Groupe de recherche universitaire sur le médicament, Departments of Medicine and Physiology, Université de Montréal, and Unité de recherche clinique, Centre de recherche et Service de néphrologie, Hôpital du Sacré-Coeur de Montréal, Québec, Canada; and Sanofi-Aventis, Paris, France

Address correspondence to: Dr. Daniel G. Bichet, Centre de recherche, Hôpital du Sacré-Coeur de Montréal, 5400 boulevard Gouin Ouest, Montréal, Québec, H4J 1C5 Canada. Phone: 514-338-2486; Fax: 514-338-2694; E-mail: daniel.bichet{at}umontreal.ca

Received for publication August 12, 2005. Accepted for publication September 28, 2005.

In many mendelian diseases, some mutations result in the synthesis of misfolded proteins that cannot reach a transport-competent conformation. In X-linked nephrogenic diabetes insipidus, most of the mutant vasopressin 2 (V2) receptors are trapped in the endoplasmic reticulum and degraded. They are unable to reach the plasma membrane and promote water reabsorption through the principal cells of the collecting ducts. Herein is reported two types of experiments: In vivo studies to assess clinically a short-term treatment with a nonpeptide V1a receptor antagonist (SR49059) and in vitro studies in cultured cell systems. In patients, SR49059 decreased 24- h urine volume (11.9 ± 2.3 to 8.2 ± 2.0 L; P = 0.005) and water intake (10.7 ± 1.9 to 7.2 ± 1.6 L; P < 0.05). Maximum increase in urine osmolality was observed on day 3 (98 ± 22 to 170 ± 52 mOsm/kg; P = 0.05). Sodium, potassium, and creatinine excretions and plasma sodium were constant throughout the study. In vitro studies indicate that the nonpeptide V1a receptor antagonist SR49059 and the V1a/V2 receptor antagonist YM087 (Conivaptan) rescued cell surface expression and function of mutant V2 receptors. Mutant V2 receptors with nonsense mutations were not affected by the treatment. Misfolded V2 receptor mutants were rescued in vitro and also in vivo by nonpeptide antagonists. This therapeutic approach could be applied to the treatment of several hereditary diseases that result from errors in protein folding and kinesis.

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