Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently, no targeted therapy is available for this disease. INVS/NPHP2 is one of the over 25 NPHP genes identified to date. In mouse, global knockout of Invs leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type-specific knockout mouse models of Invs, investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial-specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invsflox/flox;Foxd1-Cre mice, where Invs is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Invsflox/flox;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invsflox/flox;Cdh16-Cre mutant kidney, supporting a significant interaction of cilia and Invs function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in Invs mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.
Keywords: cell biology; cilia; developmental biology; fibrosis; histone deacetylase inhibitor HDACI; mouse; nephronophthisis NPHP; nphp2/Inv; polycystic kidney disease PKD.
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.
© 2023, Li, Xu et al.