2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) Erratum (v17,p591) All Versions of this Article: ASN.2005080854v1 17/1/232    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bernier, V. Articles by Bichet, D. G. Search for Related Content PubMed PubMed Citation Articles by Bernier, V. Articles by Bichet, D. G. Related Collections Related Articles

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.

Related Articles

This Month’s Highlights
J. Am. Soc. Nephrol. 2006 17: 1-2. [Full Text] [PDF]

This article has been cited by other articles:

				I. Schwieger, K. Lautz, E. Krause, W. Rosenthal, B. Wiesner, and R. Hermosilla Derlin-1 and p97/Valosin-Containing Protein Mediate the Endoplasmic Reticulum-Associated Degradation of Human V2 Vasopressin Receptors Mol. Pharmacol., March 1, 2008; 73(3): 697 - 708. [Abstract] [Full Text] [PDF]

				P. M. Conn, A. Ulloa-Aguirre, J. Ito, and J. A. Janovick G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo Pharmacol. Rev., September 1, 2007; 59(3): 225 - 250. [Abstract] [Full Text] [PDF]

				T. T. Leskela, P. M. H. Markkanen, E. M. Pietila, J. T. Tuusa, and U. E. Petaja-Repo Opioid Receptor Pharmacological Chaperones Act by Binding and Stabilizing Newly Synthesized Receptors in the Endoplasmic Reticulum J. Biol. Chem., August 10, 2007; 282(32): 23171 - 23183. [Abstract] [Full Text] [PDF]

				J. H. Robben, M. Sze, N. V. A. M. Knoers, and P. M. T. Deen Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus Am J Physiol Renal Physiol, January 1, 2007; 292(1): F253 - F260. [Abstract] [Full Text] [PDF]

				J. H. Robben, N. V. A. M. Knoers, and P. M. T. Deen Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol, August 1, 2006; 291(2): F257 - F270. [Abstract] [Full Text] [PDF]

				R. W. Schrier Body Water Homeostasis: Clinical Disorders of Urinary Dilution and Concentration J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1820 - 1832. [Full Text] [PDF]

				S. R. Hawtin Pharmacological Chaperone Activity of SR49059 to Functionally Recover Misfolded Mutations of the Vasopressin V1a Receptor J. Biol. Chem., May 26, 2006; 281(21): 14604 - 14614. [Abstract] [Full Text] [PDF]

				J. A. Shayman Thinking about Rare Kidney Diseases J. Am. Soc. Nephrol., January 1, 2006; 17(1): 15 - 16. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673