Functional Rescue of a Nephrogenic Diabetes Insipidus Causing Mutation in the V2 Vasopressin Receptor by Specific Antagonist and Agonist Pharmacochaperones
Open Access
- 25 January 2022
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Pharmacology
- Vol. 13, 811836
- https://doi.org/10.3389/fphar.2022.811836
Abstract
The urine concentrating function of the kidney is essential to maintain the water homeostasis of the human body. It is mainly regulated by the arginine-vasopressin (AVP), which targets the type 2 vasopressin receptor (V2R) in the kidney. The inability of V2R to respond to AVP stimulation leads to decreased urine concentration and congenital nephrogenic diabetes insipidus (NDI). NDI is characterized by polyuria, polydipsia, and hyposthenuria. In this study, we identified a point mutation (S127F) in the AVPR2 gene of an NDI patient, and we characterized the impaired function of the V2R mutant in HEK293 cells. Based on our data, the S127F-V2R mutant is almost exclusively located intracellularly in the endoplasmic reticulum (ER), and very few receptors were detected at the cell surface, where the receptor can bind to AVP. The overexpressed S127F-V2R mutant receptor has negligible cAMP generation capability compared to the wild-type receptor in response to AVP stimulation. Since certain misfolded mutant proteins, that are retained in the ER, can be rescued by pharmacological chaperones, we examined the potential rescue effects of two pharmacochaperones on the S127F-V2R. We found that pretreatment with both tolvaptan (an established V2R inverse agonist) and MCF14 compound (a cell-permeable high-affinity agonist for the V2R) were capable of partially restoring the cAMP generating function of the receptor in response to vasopressin stimulation. According to our data, both cell permeant agonists and antagonists can function as pharmacochaperones, and serve as the starting compounds to develop medicines for patients carrying the S127F mutation.Funding Information
- Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
- Nemzeti Kutatási Fejlesztési és Innovációs Hivatal
This publication has 46 references indexed in Scilit:
- Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney DiseaseThe New England Journal of Medicine, 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R AntagonistsOnline Journal of Public Health Informatics, 2012
- Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes InsipidusJournal of the American Society of Nephrology, 2009
- A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5′ end of Pkd1Kidney International, 2008
- Physiology and pathophysiology of the vasopressin-regulated renal water reabsorptionPflügers Archiv - European Journal of Physiology, 2008
- Analysis of interactions responsible for vasopressin binding to human neurohypophyseal hormone receptors—molecular dynamics study of the activated receptor–vasopressin–Gα systemsJournal of Peptide Science, 2006
- Nephrogenic Syndrome of Inappropriate AntidiuresisThe New England Journal of Medicine, 2005
- Current Treatments and Novel Pharmacologic Treatments for Hyponatremia in Congestive Heart FailureThe American Journal of Cardiology, 2005
- Therapeutic approaches to protein-misfolding diseasesNature, 2003