Prostaglandin Analogs and Eupatilin as Treatments for Nephronophthisis.

INTRODUCTION: Primary cilia (PCs) are sensory antennae that are present on the majority of quiescent vertebrate cells where they mediate key signaling during development and in response to environmental stimuli. Defects in PCs result in a group of heterogeneous inherited disorders with overlapping phenotypes, called ciliopathies. Nephronophthisis is an autosomal recessive tubulointerstitial kidney ciliopathy with > 25 identified genes called NPHP. Presently, no treatment exists beyond supportive care and kidney transplant, underscoring the need for novel therapies. METHODS: Using a phenotypic screening approach in cultured cell lines, we previously identified prostaglandin analogues as candidate therapeutic molecules based on their ability to rescue ciliogenesis defects in kidney tubular cells from patients with NPHP1 . Here, we investigated the potential beneficial effects of ROCK inhibitor and Eupatilin, similarly identified by other groups in different NPHP contexts, in kidney cells from patients with NPHP1 and those with IQCB1/NPHP5 as well as in a zebrafish nphp mutant line (traf3ip1/ift54). RESULTS: Eupatilin partially rescued NPHP1-associated ciliogenesis defects. Transcriptomic analyses pointed out that cell cycle progression was inhibited by Eupatilin, likely explaining its broad effects on cilia assembly. Interestingly, though ciliary defects also observed in NPHP5 patient cells were rescued by both prostaglandins and Eupatilin, only prostaglandin analogues were able to reduce pronephric cysts size in the used nphp zebrafish model. CONCLUSION: Our study indicates that these molecules can show beneficial effects across genetic contexts and shed light on their potential as therapeutic interventions for nephronophthisis.