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

Abstract

Significance 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.

Emx2 is an essential regulator of ciliated cell development across embryonic tissues

“…A decade ago, it was found that PGE 2 is important for regulating anterograde intraflagellar transport in ciliogenesis (Jin et al, 2014). Regulation of prostaglandin signaling has been recently identified as a potential treatment for the condition nephronophthisis (NPH), a rare renal ciliopathy (Garcia et al, 2022). Using Nphp1 KO mouse, a major gene important for primary cilium and cellular junctions, it was found that prostaglandin molecule PGE 1 and Taprenepag, a PGE 2 receptor agonist alleviated ciliopathy phenotypes in the Nphp1 KO mouse (Garcia et al, 2022).…”

Reducing GEF-H1 Expression Inhibits Renal Cyst Formation, Inflammation, and Fibrosis via RhoA Signaling in Nephronophthisis

“…Recently, Garcia H. et al validated prostaglandin signaling as a target of NPHP1 -defective NPHP. PGE1 treatment can decrease the upregulated RhoA activity and attenuate the renal manifestations in NPHP1 KO mice, including tubular dilatation, early upregulation of fibrosis markers and extracellular matrix components, and abnormal cilia [ 17 ].…”

“…Importantly, the pathogenesis of NPHP is not yet fully understood [ 15 ]. RhoA activation and a perturbed cytoskeleton have been observed in a variety of ciliopathies, including NPHP, suggesting that RhoA may be implicated in the pathogenesis of NPHP [ 16 , 17 ]. However, the mechanism underlying RhoA activation in ciliopathies remains unclear.…”

GeNepher data- and biobank for patients with (suspected) genetic kidney disease: rationale, design and status update

“…In this era with emerging compound identi cation which target speci c disease etiology [22][23][24][25], a dataset with patients with rare kidney disease diagnoses, from whom biological materials can be requested (for instance for ex vivo research) is of great value for translational research. Biological materials can also be used for high throughput drug testing and for individualization of drugs: in vitrotesting speci c (approved) drugs to see which drug works for an individual patient / variant.…”