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Abstract: SA-PO588

PBI-4050 Reduces Systemic Inflammation, Electrolyte Disturbances, and Renal Injury in Mice with Sepsis-Induced AKI: Role of GPR84

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Thibodeau, Jean-Francois, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Holterman, Chet E., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Cloutier, Marie-Pier, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Simard, Jean-Christophe, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Gagnon, Lyne, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Laurin, Pierre, Prometic Biosciences Inc., Laval, Quebec, Canada
  • Hébert, Richard L., University of Ottawa, Ottawa, Ontario, Canada
  • Leblond, Francois A., Prometic Biosciences Inc., Laval, Quebec, Canada
  • Kennedy, Chris R., University of Ottawa, Ottawa, Ontario, Canada
Background

PBI-4050, Prometic Biosciences Inc.’s lead drug candidate, exerts anti-inflammatory and anti-fibrotic effects in several diabetic and non-diabetic models of kidney injury through modulation of GPR40 and GPR84 fatty acid receptors. Primarily in macrophages and fibroblasts, we have shown that the pro-inflammatory GPR84 receptor is induced in cultured human renal cells including proximal tubule epithelial cells (hPTEC) and podocytes (hPod) stimulated with bacterial lipopolysaccharides (LPS). We therefore queried the impact of PBI-4050 in a model of endotoxemia-induced AKI and evaluated the role of GPR84 in this regard.

Methods

Eight-week old male C57BL/6 mice were treated with PBI-4050 (200 mg/kg BW, p.o.) for 14 days followed by LPS (10 mg/kg, i.p.)-challenge and sacrificed 24 hours later.

Results

AKI was confirmed as LPS led to a rapid rise in plasma creatinine and urea, which were significantly decreased in PBI-4050-treated mice. LPS-induced hyperphosphatemia, hyperkalemia, hypocalcaemia and hypoglycemia, were also significantly improved by PBI-4050. Circulating levels of several major pro-inflammatory cytokines, including IL-1β, IL-6, MCP-1, TNFα, CXCL-1 and Rantes (CCL5) correlated with creatinine levels, and were significantly decreased by PBI-4050 in LPS mice. Moreover, PBI-4050 reduced LPS-induced albuminuria and albuminemia. Histological assessment revealed tubular cell injury was reduced and PT-megalin expression improved with PBI-4050, as was peri-glomerular and tubulointerstitial α-SMA expression. In a pilot study, GPR84-/- mice challenged with 24 hours LPS showed modest yet significant improvements in renal function. LPS caused GPR84 induction in cultured hPTECs and hPODs. PBI-4050 treatment in LPS-stimulated hPTEC and hPods decreased pro-inflammatory gene expression including MCP-1, IL-6 and IL-8.

Conclusion

Taken together, PBI-4050 improves systemic inflammation and indicators of glomerular and tubular injury in a model of LPS-induced AKI partly through GPR84 and may directly target specific renal cell types including PTEC’s and podocytes.

Funding

  • Commercial Support