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

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 Invs(flox/flox);Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invs(flox/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 Invs(flox/flox);Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invs(flox/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.

Automated summary

This study reveals the critical role of renal epithelial cilia in NPHP and suggests the possibility of repurposing the histone deacetylase inhibitor VPA for NPHP treatment. Cell-type-specific knockout mouse models of the Invs gene were generated and characterized, and it was found that the absence of cilia leads to increased severity of renal cyst formation and interstitial fibrosis. The study also shows a significant interaction between cilia and Invs function in vivo, and the histone deacetylase inhibitor VPA reduces cyst burden, decreases cell proliferation, and ameliorates kidney function decline in Invs mutant mice.