Evaluation of Prostaglandin Receptor Agonists and Eupatilin in the Context of Nephronophthisis
Abstract
Background
Primary cilia are sensory antennas 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 primary cilia result in a group of heterogeneous inherited disorders with overlapping phenotypes, called ciliopathies. Nephronophthisis is an autosomal recessive tubulo-interstitial kidney ciliopathy with more than 25 identified genes calledNPHP. 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 fromNPHP1patients. Here, we have investigated the potential beneficial effects of ROCK inhibitors and Eupatilin, similarly identified by other groups in different NPHP contexts, in kidney cells fromNPHP1andIQCB1/NPHP5patients as well as in a zebrafishNPHPmutant line (traf3ip1/ift54).
Results
Eupatilin partially rescuedNPHP1-associated ciliogenesis defects. Transcriptomic analyses pointed out that cell cycle progression was inhibited by Eupatilin, likely explaining its broad effects on cilia assembly. Interestingly, while ciliary defects also observed inNPHP5patient cells were rescued by both prostaglandins and Eupatilin, only prostaglandin analogues were able to reduce pronephric cysts size in the usednphpzebrafish 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.
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