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

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key fu...

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Autores principales: Garcia, Hugo, Serafin, Alice S., Silbermann, Flora, Porée, Esther, Viau, Amandine, Mahaut, Clémentine, Billot, Katy, Birgy, Éléonore, Garfa-Traore, Meriem, Roy, Stéphanie, Ceccarelli, Salomé, Mehraz, Manon, Rodriguez, Pamela C., 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170064/
https://www.ncbi.nlm.nih.gov/pubmed/35482924
http://dx.doi.org/10.1073/pnas.2115960119
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author Garcia, Hugo
Serafin, Alice S.
Silbermann, Flora
Porée, Esther
Viau, Amandine
Mahaut, Clémentine
Billot, Katy
Birgy, Éléonore
Garfa-Traore, Meriem
Roy, Stéphanie
Ceccarelli, Salomé
Mehraz, Manon
Rodriguez, Pamela C.
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
author_facet Garcia, Hugo
Serafin, Alice S.
Silbermann, Flora
Porée, Esther
Viau, Amandine
Mahaut, Clémentine
Billot, Katy
Birgy, Éléonore
Garfa-Traore, Meriem
Roy, Stéphanie
Ceccarelli, Salomé
Mehraz, Manon
Rodriguez, Pamela C.
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
author_sort Garcia, Hugo
collection PubMed
description Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E(1) (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E(2) receptor agonist, alleviated the severe retinopathy observed in Nphp1(−/−) mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E(2) receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies.
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spelling pubmed-91700642022-06-07 Agonists of prostaglandin E(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies Garcia, Hugo Serafin, Alice S. Silbermann, Flora Porée, Esther Viau, Amandine Mahaut, Clémentine Billot, Katy Birgy, Éléonore Garfa-Traore, Meriem Roy, Stéphanie Ceccarelli, Salomé Mehraz, Manon Rodriguez, Pamela C. 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 Proc Natl Acad Sci U S A Biological Sciences Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E(1) (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E(2) receptor agonist, alleviated the severe retinopathy observed in Nphp1(−/−) mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E(2) receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies. National Academy of Sciences 2022-04-28 2022-05-03 /pmc/articles/PMC9170064/ /pubmed/35482924 http://dx.doi.org/10.1073/pnas.2115960119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Garcia, Hugo
Serafin, Alice S.
Silbermann, Flora
Porée, Esther
Viau, Amandine
Mahaut, Clémentine
Billot, Katy
Birgy, Éléonore
Garfa-Traore, Meriem
Roy, Stéphanie
Ceccarelli, Salomé
Mehraz, Manon
Rodriguez, Pamela C.
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
Agonists of prostaglandin E(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies
title Agonists of prostaglandin E(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies
title_full Agonists of prostaglandin E(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies
title_fullStr Agonists of prostaglandin E(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies
title_full_unstemmed Agonists of prostaglandin E(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies
title_short Agonists of prostaglandin E(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies
title_sort agonists of prostaglandin e(2) receptors as potential first in class treatment for nephronophthisis and related ciliopathies
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170064/
https://www.ncbi.nlm.nih.gov/pubmed/35482924
http://dx.doi.org/10.1073/pnas.2115960119
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