Kidney Week

Abstract: SA-PO569

PBI-4050 Reduces Renal Injury in a Mouse Model of Aristolochic Acid-Induced Nephropathy

Session Information

• Glomerular Diseases: Fibrosis, Extracellular Matrix
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

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

Jean-Francois Thibodeau,

• Blais, Amélie, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Amélie Blais,

• Sarra-Bournet, François, Prometic Biosciences Inc., Laval, Quebec, Canada

François Sarra-Bournet,

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

Brigitte Grouix,

• Gutsol, Alex, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Alex Gutsol,

• Leduc, Martin, Prometic Biosciences Inc., Laval, Quebec, Canada

Martin Leduc,

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

Francois A. Leblond,

• Hébert, Richard L., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Richard L. Hébert,

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

Lyne Gagnon,

• Kennedy, Chris R., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Chris R. Kennedy,

Background

PBI-4050 is a novel therapeutic compound with excellent safety and efficacy profiles in both experimental and clinical settings. Treatment with PBI-4050, a dual GPR40 agonist and GPR84 antagonist, is beneficial in diseases where sustained inflammation and fibrosis are involved, including chronic kidney disease (CKD). Here we used the aristolochic acid (AA) model of CKD and tested whether treatment with PBI-4050 could mitigate renal injury progression.

Methods

Eight-week old male C57BL/6 mice were challenged with AA (4 days, 3.5 mg/kg/day, i.p.) and were treated with PBI-4050 (200 mg/kg/day, p.o.) or vehicle (H₂O) seven days later for four weeks. Plasma creatinine was measured weekly by HPLC. Twenty-four hour urine collection was performed at endpoint. Tubulointerstitial injury was assessed using Sirius-red and PAS-stained kidney sections. Lipid accumulation was observed using Oil Red-O stained frozen kidney sections.

Results

At endpoint, renal function was significantly improved in PBI-4050 treated AA-mice, as plasma creatinine and urea were reduced compared to vehicle treated mice. This was accompanied by significant improvements in polyuria and tubular function as fractional excretion of Na⁺, K⁺, Ca²⁺ was maintained by PBI-4050. Moreover, AA-induced reduction in hematocrit was significantly improved as early as one week-post treatment with PBI-4050 and maintained until endpoint. Consistent with improved renal function, tubulointerstitial fibrosis (% collagen area) was apparent in AA-mice and was significantly reduced in PBI-4050-treated mice. Interestingly, AA-challenged mice had significant lipid deposition in kidney tissue along with reduced PGC1α mRNA expression, and this effect was also improved by PBI-4050. Finally, inflammatory cell infiltration and F4/80 mRNA levels were decreased in PBI-4050 treated AA-mice.

Conclusion

Overall, treatment with PBI-4050 improved several key renal functional and structural abnormalities in AA-induced CKD including anemia, fibrosis, renal lipid handling and functional decline. Results from the above and previous studies suggest treatment with PBI-4050 has the potential to slow the progression of CKD due to various diseases with different etiologies.

Funding

• Commercial Support – Prometic Life Sciences Inc.