Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.

One of the most common causes of kidney failure in children and young adults is nephronophthisis. This genetic disease causes cysts and tissue scarring in the kidneys, leading to excessive urine production and extreme tiredness. Unfortunately, there is no targeted therapy available for this condition. Scientists do not fully understand how genetic mutations lead to these symptoms. Previous research in mice showed that blocking the gene for a protein called INVS recreated signs similar to nephronophthisis. However, it is not clear how the different cell types in the kidneys are involved. Previous results suggest that cilia, the hair-like projections on the surface of cells, could be involved in developing cysts in nephronophthisis. To understand how the disease is driven, Li, Xu et al. created a range of genetically modified mice with INVS missing in different cell types. When INVS was removed from cells that line the kidney tubules, the mice developed scarring and cysts. By contrast, there were no symptoms when connective tissue cells were lacking INVS. When Li, Xu et al. removed the cilia from the cells, it helped to reduce the negative impact of the loss of INVS. In addition, a drug called valproic acid reduced the cysts and tissue scarring, and slowed kidney decline in the mutant mice, suggesting the possibility of repurposing this drug for nephronophthisis treatment. These results could help researchers to study other conditions that are influenced by the health of cilia. Future work on nephronophthisis will be needed to understand how INVS causes the disease and the mechanism for the benefits of valproic acid.