Kidney Week

Abstract: FR-PO472

Activation of the Free-Fatty Acid Receptor GPR40 Improves Anemia in Mouse Models of Kidney Disease via a Novel EPO-Independent Mechanism of Action

Session Information

• Anemia and Iron Metabolism: Basic
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Anemia and Iron Metabolism

• 201 Anemia and Iron Metabolism: Basic

Authors

• Thibodeau, Jean-Francois, Prometic Biosciences Inc., Laval, Quebec, Canada

Jean-Francois Thibodeau,

• Holterman, Chet E., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Chet E. Holterman,

• Laurin, Pierre, Prometic Biosciences Inc., Laval, Quebec, Canada

Pierre Laurin,

• Hébert, Richard L., University of Ottawa, Ottawa, Ontario, Canada

Richard L. Hébert,

• Kennedy, Chris R., University of Ottawa, Ottawa, Ontario, Canada

Chris R. Kennedy,

• Grouix, Brigitte, Prometic Biosciences Inc., Laval, Quebec, Canada

Brigitte Grouix,

• Gagnon, Lyne, Prometic Biosciences Inc., Laval, Quebec, Canada

Lyne Gagnon,

Background

The prevalence of anemia increases with the progression of chronic kidney disease (CKD) and leads to reduced quality of life and increased cardiovascular risk. Yet, the use of erythropoiesis stimulating agents is associated with negative outcomes in CKD patients. Here we present an alternative pathway for the treatment of anemia secondary to kidney disease through activation of GPR40, in mediating in vitro stimulation of bone marrow cells, particularly the colony-forming-unit-erythrocytes (CFU-E) generation; and the anti-anemic effects of PBI-4050 in models of renal injury.

Methods

In vitro, murine bone marrow cells were assayed for CFU-E in the presence or absence of PBI-4050 (agonist of GPR40) and/or GW1100 (GPR40 antagonist). PBI-4050 was tested in ischemia-reperfusion (IR) AKI in WT mice. In addition, we used an adenine-induced CKD model whereby male wild type (WT) and GPR40^-/- mice were fed a diet supplemented with 0.25% adenine for one week and treated for three weeks with PBI-4050 (200 mg/kg).

Results

PBI-4050 increased the formation of CFU-E in a GPR40 dependent manner as GW1100 blocked this increase. In addition, GPR40 antagonism led to a significant decrease in CFU-E counts. Furthermore, PBI-4050 showed comparable activity to EPO regarding CFU-E count. After 14 days following IR-AKI, PBI-4050 maintained hematocrit. In adenine-CKD mice, Hct, Hb and mean corpuscular volume were significantly decreased in CKD-mice, while PBI-4050 maintained these levels and led to significantly higher plasma erythropoietin levels. In parallel, signs of anemia were present to similar degrees in both untreated WT and GPR40^-/- mice. Interestingly, PBI-4050 treatment in adenine-fed GPR40^-/- mice failed to improve Hct levels.

Conclusion

Taken together, our data suggest treatment of anemia through a novel alternative pathway which is EPO-independent. Treatment with PBI-4050 may provide therapeutic benefit by maintaining adequate Hct and Hb levels, while also improving renal and cardiovascular outcomes.

Funding

• Commercial Support – Prometic Life Sciences Inc.