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Impaired Protein Stability of 11-Hydroxysteroid Dehydrogenase Type 2: A Novel Mechanism of Apparent Mineralocorticoid Excess

Department of Nephrology and Hypertension, University of Bern, Bern, Switzerland

Address correspondence to: Dr. Alex Odermatt, Department of Nephrology and Hypertension, University of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland. Phone: +41-31-632-9438; Fax: +41-31-632-9444; E-mail: alex.odermatt{at}dkf.unibe.ch

Received for publication November 13, 2006. Accepted for publication January 4, 2007.

Apparent mineralocorticoid excess (AME) is a severe form of hypertension that is caused by impaired activity of 11-hydroxysteroid dehydrogenase type 2 (11-HSD2), which converts biologically active cortisol into inactive cortisone. Mutations in HSD11B2 result in cortisol-induced activation of mineralocorticoid receptors and cause hypertension with hypokalemia, metabolic alkalosis, and suppressed circulating renin and aldosterone concentrations. This study uncovered the first patient with AME who was described in the literature, identified the genetic defect in HSD11B2, and provided evidence for a novel mechanism of reduced 11-HSD2 activity. This study identified a cluster of amino acids (335 to 339) in the C-terminus of 11-HSD2 that are essential for protein stability. The cluster includes Tyr³³⁸, which is mutated in the index patient, and Arg³³⁵ and Arg³³⁷, previously reported to be mutated in hypertensive patients. It was found that wild-type 11-HSD2 is a relatively stable enzyme with a half-life of 21 h, whereas that of Tyr³³⁸His and Arg³³⁷His was 3 and 4 h, respectively. Enzymatic activity of Tyr³³⁸His was partially retained at 26°C or in the presence of the chemical chaperones glycerol and dexamethasone, indicating thermodynamic instability and misfolding. The results provide evidence that the degradation of both misfolded mutant Tyr³³⁸His and wild-type 11-HSD2 occurs through the proteasome pathway. Therefore, impaired 11-HSD2 protein stability rather than reduced gene expression or loss of catalytic activity seems to be responsible for the development of hypertension in some individuals with AME.

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