A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors
| Autor: | Jean-Francois Thibodeau, Alexandre Laverdure, Kathy Hince, Richard L. Hébert, Alex Gutsol, William Gagnon, Martin Leduc, Eldjonai Kamto, Liette Gervais, Shaun D. Abbott, Christopher R.J. Kennedy, Francois A. Leblond, Jonathan Richard, Pierre Laurin, Chet E. Holterman, Alexandra Felton, Ming-Zhi Zhang, François Sarra-Bournet, Mikaël Tremblay, Jugurtha Ouboudinar, Lilianne Geerts, Christopher Penney, Lyne Gagnon, Jocelyn Dupuis, Jean-Christophe Simard, Jean-Simon Duceppe, Quang Trinh Nguyen, Marie-Pier Cloutier, Raymond C. Harris, Angelino Calderone, Brigitte Grouix, Boulos Zacharie, Sylvie Létourneau |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification endocrine system Kidney business.industry Fatty acid Pharmacology medicine.disease Pathology and Forensic Medicine 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure chemistry Fibrosis Free fatty acid receptor 1 Knockout mouse GPR84 medicine Receptor business Kidney disease |
| Zdroj: | The American Journal of Pathology. 188:1132-1148 |
| ISSN: | 0002-9440 |
| Popis: | Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein–coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40 - and Gpr84 -knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases. |
| Databáze: | OpenAIRE |
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