An event that could change the approach to treating rare kidney diseases has taken place in the laboratories of Barcelona. A group of molecular biologists from the Centre for Genomic Regulation (CRG) unexpectedly discovered that a drug long used to treat liver cirrhosis and heart conditions can restore kidney function in patients with nephrogenic diabetes insipidus.
During the experiments, the scientists focused on the V2R receptor, which is encoded by the AVPR2 gene. It is mutations in this segment of DNA that cause the kidneys to stop responding to vasopressin, resulting in the body losing a large amount of fluid. The researchers decided to test whether an already existing medication could stabilize the defective receptor proteins so they could resume their function.
The results proved impressive: the drug helped restore V2R receptor activity in 87% of cases involving the most common mutations that cause the disease. Moreover, the analysis showed that the medication may neutralize the effects of 835 out of 965 potentially dangerous changes in the structure of this protein. This paves the way for treatment for the majority of patients with such genetic disorders.
The drug’s mechanism of action turned out to be quite unusual. The molecule binds to a partially formed receptor inside the cell, stabilizing it and helping it pass the cell’s ‘quality control’ checkpoints. As a result, the protein reaches the membrane and begins to capture the hormone vasopressin, allowing the kidneys to resume their water-retention function.
The discovery by Spanish scientists is not limited to treating nephrogenic diabetes insipidus. Researchers are confident that a similar approach could be used to stabilize other membrane proteins affected by point mutations in various hereditary diseases. This may significantly speed up the development of new drugs for a range of genetic disorders that currently lack effective therapy.
