Kidney Week

Abstract: SA-PO819

PBI-4050 Signals via GPR40 to Decrease Adenine-Induced Tubulointerstitial Injury and ER Stress

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

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,

• Simard, Jean-Christophe, Prometic Biosciences Inc., Laval, Quebec, Canada

Jean-Christophe Simard,

• Leblond, Francois A., Prometic Biosciences Inc., Laval, Quebec, Canada

Francois A. Leblond,

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

Brigitte Grouix,

• Nasrallah, Rania, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Rania Nasrallah,

• 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,

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

Lyne Gagnon,

Background

PBI-4050, a novel first-in-class orally active compound currently in clinical phase III in IPF patients, exerts antifibrotic effects in several organs via a novel mechanism of action. In the kidney, PBI-4050 exerts its antifibrotic effects primarily through GPR40 activation. The aim of this study was to further examine the effects of PBI-4050 in both WT and GPR40^-/- mice on adenine-induced tubulointerstitial fibrosis, inflammation and the unfolded protein response pathway, all of which contribute to CKD progression.

Methods

Adenine-induced CKD was achieved in eight-week old male C57BL/6 mice fed a diet supplemented with 0.25% adenine. After one week, PBI-4050 (50, 100, 200 mg.kg^-1day) or vehicle was administered daily by oral-gavage for three weeks. In parallel, eight-week old wild-type and GPR40^-/- mice were also subjected to adenine-CKD, with or without a PBI-4050 (200 mg.kg^-1 day) treatment.

Results

PBI-4050 treatment reduced adenine-induced polyuria and maintained urine osmolality. Plasma urea and creatinine were significantly increased four and two-fold respectively in vehicle treated mice, while PBI-4050 decreased these values. PBI-4050 treatment decreased adenine-mediated renal fibrotic lesions in a dose dependent manner. Accordingly, α-SMA and fibronectin expression were also reduced by PBI-4050 as well as several pro-inflammatory genes. Moreover, renal ER-stress and pro-apoptotic markers were significantly reduced by PBI-4050 in adenine fed mice. In parallel, GPR40^-/- mice given adenine had increased tubulointerstitial injury, exacerbated renal function and ER-stress associated protein expression compared to WT mice. PBI-4050 treatment in adenine-fed GPR40^-/- mice failed to reduce anemia, tubulointerstitial injury and ER-stress.

Conclusion

PBI-4050 treatment decreased the severity of several adenine-induced sequelae including tubular injury, tubulointerstitial fibrosis, anemia, apoptosis and ER-stress. The GPR40 receptor mediates PBI-4050’s beneficial effects in this model. Taken together, these data reinforce PBI-4050’s use as a renoprotective therapy and identify important pathways involved.

Funding

• Commercial Support – Prometic Life Sciences Inc.