PBI-4050 Improves Metabolic Regulation and Diabetic Nephropathy through Reduction of ER Stress, Pro-Inflammatory/Fibrotic Markers, Galectin-3 Expression, and Inflammatory Cell Infiltration in ob/ob Mouse Model

Background: PBI-4050 displays anti-inflammatory/fibrotic properties with metabolic regulation. PBI-4050 has been shown to reduce glycated hemoglobin levels, and different biomarkers related to kidney and heart injury in a phase II open label clinical trial in patients suffering from type 2 diabetes with metabolic syndrome. PBI-4050 has also completed with success an open label phase II clinical trial in patients with idiopathic pulmonary fibrosis (IPF) and in patients with Alstrom Syndrome. The aim of this study was to investigate the effect of PBI-4050 on diabetic nephropathy in leptin deficient ob/ob mice, a model of type 2 diabetes and metabolic syndrome. Methods: ob/ob mice were treated with vehicle or PBI-4050 (200 mg/kg, oral once a day) from day 1 to 105. OGTT, triglycerides, adiponectin and serum insulin levels, as well as inflammatory cell infiltration and pro-inflammatory/fibrotic gene expression and histology of kidney and white adipose tissue (WAT) were examined. Results: PBI-4050 improved glucose metabolism, reduced serum triglycerides and insulin levels, and increased serum adiponectin levels. In kidneys, PBI-4050 reduced ER stress (p-PERK, ATF-6, CHOP and p-IRE1). Furthermore, PBI-4050 reduced α-SMA, fibronectin and CTGF gene expression. Pro-inflammatory/remodeling markers expression (MRC-1, MCP-1 and MMP-2) were also reduced with PBI-4050 treatment. Moreover, histological analysis revealed that PBI-4050 reduced collagen deposition in glomeruli. Specific immunostaining also showed that PBI-4050 significantly reduced galectin-3 expression in kidney and WAT. Finally, PBI-4050 reduced the expression levels of inflammatory cell infiltration markers (Ly6G and F4/80) in kidney. Conclusions: These results suggest that PBI-4050 is a strong potential candidate for the treatment of metabolic diseases and related diabetic nephropathy. Disclosure J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Richard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..