Abstract: TH-OR085
Fatty Acid Receptors GPR40/GPR84: Two Promising Targets in Kidney Fibrosis
Session Information
- Glomerular Diseases: Fibrosis and Extracellular Matrix
November 07, 2019 | Location: Salon C, Walter E. Washington Convention Center
Abstract Time: 05:54 PM - 06:06 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Gagnon, Lyne, Prometic Biosciences Inc., Laval, Quebec, Canada
- Thibodeau, Jean-Francois, Prometic Biosciences Inc., Laval, Quebec, Canada
- Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Sarra-Bournet, François, Prometic Biosciences Inc., Laval, Quebec, Canada
- Hince, Kathy, Prometic Biosciences Inc., Laval, Quebec, Canada
- Tremblay, Mikaël, Prometic Biosciences Inc., Laval, Quebec, Canada
- Geerts, Lilianne, Prometic Biosciences Inc., Laval, Quebec, Canada
- Kennedy, Chris R., Kidney Research Centre, Ottawa, Ontario, Canada
- Hébert, Richard L., Kidney Research Centre, Ottawa, Ontario, Canada
- Gutsol, Alex, Kidney Research Centre, Ottawa, Ontario, Canada
- Holterman, Chet E., Kidney Research Centre, Ottawa, Ontario, Canada
- Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Grouix, Brigitte, Prometic Biosciences Inc., Laval, Quebec, Canada
Background
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 stimulated by free fatty acid ligands. Although both receptors have been associated with metabolic regulation and inflammation, they have not been previously linked to organ fibrosis. The dual GPR40 agonist/GPR84 antagonist PBI-4050 is a novel antifibrotic drug candidate entering phase III in idiopathic pulmonary fibrosis (IPF) and Alström syndrome.
The aim of this study was to determine the role of GPR40 and GPR84 receptors and the effect of PBI-4050 treatment in models of acute kidney injury (AKI) and chronic kidney disease (CKD).
Methods
PBI-4050 was tested in cells involved in fibrosis (macrophages, fibroblasts and epithelial cells) and in various animal models of CKD/DKD (5/6-nephrectomized rat, db/db and db/db eNOS-/- mice, adenine-induced CKD), AKI (IRI, LPS, UUO, doxorubicin) and in GPR40- and GPR84-knockout mice.
Results
PBI-4050 acts on cells involved in the fibrotic pathway: macrophages, fibroblasts and epithelial cells by regulating cytokines, fibrotic and remodeling markers. GPR40 is also expressed in proximal tubules and collecting duct while GPR84 is mainly expressed in podocytes. In experiments using either GPR40- or GPR84-knockout mice in models of kidney fibrosis (UUO, IRI, and adenine-induced CKD), GPR40 was found protective and GPR84 deleterious. Through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in other models of AKI (doxorubicin, LPS) and CKD/DKD (5/6-nephrectomy, db/db mice). Moreover, in two phase II clinical trials (type 2 diabetes with metabolic syndrome, Alström syndrome) involving a total of 36 patients, PBI-4050 reduced kidney injury urinary biomarkers.
Conclusion
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 kidney diseases.
Funding
- Commercial Support –