Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus

Area of Science:

• Biochemistry
• Pharmacology
• Nephrology

Background:

• Mendelian diseases can arise from misfolded proteins, such as mutant vasopressin 2 (V2) receptors in X-linked nephrogenic diabetes insipidus.
• These misfolded V2 receptors are often trapped in the endoplasmic reticulum, preventing water reabsorption and leading to the disease.

Purpose of the Study:

• To investigate the therapeutic potential of nonpeptide receptor antagonists in correcting misfolded V2 receptors.
• To assess the clinical efficacy of a V1a receptor antagonist (SR49059) in patients with X-linked nephrogenic diabetes insipidus.

Main Methods:

• In vivo studies involving short-term treatment of patients with SR49059.
• In vitro studies using cultured cell systems to evaluate the effects of SR49059 and YM087 (Conivaptan) on mutant V2 receptors.

Main Results:

• In patients, SR49059 significantly reduced 24-hour urine volume and water intake, while increasing urine osmolality.
• In vitro, SR49059 and Conivaptan rescued cell surface expression and function of misfolded V2 receptor mutants, but not those with nonsense mutations.
• Nonpeptide antagonists demonstrated efficacy in rescuing misfolded V2 receptor mutants both in vitro and in vivo.

Conclusions:

• Nonpeptide V1a and V1a/V2 receptor antagonists can rescue misfolded V2 receptor mutants, offering a potential therapeutic strategy.
• This approach holds promise for treating hereditary diseases characterized by protein misfolding and impaired protein transport, including X-linked nephrogenic diabetes insipidus.