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

Area of Science:

• Nephrology
• Genetics
• Cell Biology

Background:

• Nephronophthisis (NPHP) is a genetic ciliopathy causing kidney fibrosis and cysts, leading to end-stage renal disease in young individuals.
• Currently, no targeted therapies exist for NPHP, necessitating research into disease mechanisms and potential treatments.
• The gene INVS/NPHP2 is implicated in NPHP, but the specific cellular contributions and interactions leading to fibrosis and cysts are not fully understood.

Purpose of the Study:

• To investigate the cell-type-specific roles of INVS in kidney development and NPHP pathogenesis.
• To explore the interplay between epithelial cysts and interstitial fibrosis in NPHP.
• To evaluate the therapeutic potential of valproic acid (VPA) in an NPHP mouse model.

Main Methods:

• Generation and characterization of cell-type-specific INVS knockout mouse models.
• Analysis of renal phenotypes, including cyst formation, fibrosis, and cell proliferation.
• Assessment of the impact of genetic cilia removal on NPHP phenotypes.
• Evaluation of VPA treatment on NPHP disease progression and kidney function.

Main Results:

• Epithelial-specific INVS deletion caused renal cysts and severe fibrosis, while stromal deletion had no effect, indicating crucial epithelial-stromal crosstalk.
• Increased cell proliferation and myofibroblast activation preceded cyst formation.
• Genetic removal of cilia partially suppressed NPHP phenotypes, suggesting interaction with INVS function.
• VPA treatment reduced cyst burden, decreased cell proliferation, and improved kidney function in INVS mutant mice.

Conclusions:

• Renal epithelial cilia play a critical role in NPHP pathogenesis.
• Epithelial-stromal crosstalk is a significant factor in NPHP.
• Valproic acid (VPA) demonstrates therapeutic potential for NPHP and warrants further investigation for clinical repurposing.