Abstract: FR-PO378

PBI-4050 Reduces Renal Injury and Anemia in a Mouse Model of Adenine-Induced CKD

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Thibodeau, Jean-Francois, Ottawa Hospital, Ottawa, Ontario, Canada
  • Kamto, Eldjonai, Ottawa Hospital, Ottawa, Ontario, Canada
  • Holterman, Chet E., Ottawa Hospital, Ottawa, Ontario, Canada
  • Nasrallah, Rania, Ottawa Hospital, Ottawa, Ontario, Canada
  • Gutsol, Alex, Ottawa Hospital, Ottawa, Ontario, Canada
  • Laurin, Pierre, Prometic BioSciences Inc., Laval, Quebec, Canada
  • Hebert, Richard L., Ottawa Hospital, Ottawa, Ontario, Canada
  • Kennedy, Chris R., Ottawa Hospital, Ottawa, Ontario, Canada
  • Gagnon, Lyne, Prometic BioSciences Inc., Laval, Quebec, Canada
Background

PBI-4050, a novel first-in-class orally active compound currently in clinical phase Ib/II in CKD patients, exerts antifibrotic effects via a novel mechanism of action. Through targeting of specific receptors expressed in proximal tubule cells, fibroblasts and macrophages, PBI-4050 decreases inflammation and fibrosis. The aim of this study was to investigate the effects of PBI-4050 in a model of adenine-induced CKD.

Methods

Eight-week old male C57BL/6 mice were fed standard chow, or a diet supplemented with 0.25% adenine. Following one week of adenine diet, daily doses of PBI-4050 (200 mg/kg) or water (vehicle) were administered by oral-gavage for three weeks. Longitudinal renal function was assessed by plasma creatinine via HPLC. At endpoint, blood analysis, plasma electrolyte and erythropoietin levels were measured in blood obtained by cardiac puncture. Tubulointerstitial inflammation/fibrosis and overall renal injury score was assessed in Masson’s trichrome and PAS-stained kidney sections. Pro-inflammatory and pro-fibrotic gene expression and fibronectin expression were measured in kidney cortex samples by qPCR and western immunoblotting respectively.

Results

PBI-4050 treatment reduced adenine-induced polyuria and maintained urine osmolality. Renal function assessed by plasma urea and creatinine were significantly increased four and two-fold respectively in vehicle treated mice, while PBI-4050 lowered these values. Hematocrit, hemoglobin and mean corpuscular volume were significantly decreased in CKD-mice, while PBI-4050 maintained these levels in addition to increasing plasma erythropoietin levels. Renal pro-inflammatory gene expression was equally upregulated in both adenine-groups, while. Masson’s trichrome staining, α-SMA mRNA and fibronectin protein expression were significantly upregulated in vehicle treated mice, and were decreased with PBI-4050. PAS-staining revealed decreased tubular injury and cyst formation in the adenine+PBI-4050 group compared to adenine+vehicle.

Conclusion

PBI-4050 treatment for three weeks decreased the severity of several adenine-induced sequelae including tubular injury, tubulointerstitial fibrosis and anemia. Taken together, these data reinforce its use as a potential renoprotective therapy.

Funding

  • Commercial Support