Agonists of prostaglandin E 2 receptors as potential first in class treatment for nephronophthisis and related ciliopathies

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Garcia, Hugo | Serafin, Alice | Silbermann, Flora | Porée, Esther | Viau, Amandine | Mahaut, Clémentine | Billot, Katy | Birgy, Éléonore | Garfa-Traore, Meriem | Roy, Stéphanie | Ceccarelli, Salomé | Mehraz, Manon | Rodriguez, Pamela | Deleglise, Bérangère | Furio, Laetitia | Jabot-Hanin, Fabienne | Cagnard, Nicolas | del Nery, Elaine | Fila, Marc | Sin-Monnot, Soraya | Antignac, Corinne | Lyonnet, Stanislas | Krug, Pauline | Salomon, Rémi | Annereau, Jean-Philippe | Benmerah, Alexandre | Delous, Marion | Briseño-Roa, Luis | Saunier, Sophie

Edité par CCSD ; National Academy of Sciences -

International audience. Juvenile nephronophthisis (NPH) is a renal ciliopathy due to a dysfunction of primary cilia for which no curative treatment is available. This paper describes the identification of agonists of prostaglandin E 2 receptors as a potential therapeutic approach for the most common NPHP1 -associated ciliopathies. We demonstrated that prostaglandin E 1 rescues defective ciliogenesis and ciliary composition in NPHP1 patient urine-derived renal tubular cells and improves ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 −/− mouse models. In addition, Taprenepag alleviates the severe retinopathy observed in Nphp1 −/− mice. Finally, transcriptomic analyses pointed out several pathways downstream the prostaglandin receptors as cell cycle progression, extracellular matrix, or actin cytoskeleton organization. Altogether, our findings provide an alternative for treatment of NPH.

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