482-P: The GLP-1 Receptor Agonist Liraglutide Improves Glomerular Filtration Rate, Renal Inflammation, and Fibrosis in the Type 2 Diabetic SDT Fatty Rat

Abstract

The Glucagon-Like Peptide 1 (GLP-1) receptor agonist liraglutide (LIRA) may reduce the rate of development and progression of diabetic kidney disease in type 2 diabetic patients. To evaluate its impact on kidney function, we evaluated the effects of LIRA on glomerular filtration rate (GFR), in both the hyperfiltration and GFR decline phases in the Spontaneously Diabetic Torii (SDT) fatty rat, a preclinical model of type 2 diabetes. SDT fatty male rats were treated subcutaneously, once daily with vehicle or LIRA 0.4mg/kg for 10 weeks. To measure the effects of LIRA on glomerular hyperfiltration, rats were injected with FITC-sinistrin at 4 weeks of treatment to measure GFR. After 5 weeks of treatment, rats underwent unilateral nephrectomy and were put on a 0.3% salt diet to induce a GFR decline for the last weeks of treatment, then GFR was measured at 10 weeks of treatment. Urine biochemistry and kidney histology analysis were also performed. Compared with vehicle, LIRA resulted in significant body weight loss and lower body weight. LIRA also reduced blood glucose levels significantly by up to ∼20%, as expected. During the hyperfiltration phase, LIRA attenuated hyperfiltration, with a 19% lower GFR vs. vehicle (vehicle: 21 ± 1.1 mL/min/kg; LIRA: 17.1 ± 1.0 mL/min/kg, p<0.05 vs. vehicle). In vehicle treated animals, unilateral nephrectomy and 0.3% salt diet induced a major reduction (-56%) in GFR, as expected. After 10 weeks of treatment, LIRA markedly attenuated this GFR decline (vehicle: 9.3 ± 0.5 mL/min/kg; LIRA: 13.3 ± 0.9 mL/min/kg, p<0.001 vs. vehicle). In line with the benefits observed on GFR, LIRA lowered urine albumin to creatinine ratio both in the hyperfiltration and GFR decline phases. Moreover, histology analysis showed that LIRA significantly reduced kidney inflammation and fibrosis scores, as compared with vehicle. In conclusion, LIRA shows significant benefits on GFR, renal inflammation and fibrosis in the SDT fatty rat model. Disclosure F. Briand: Employee; Self; Physiogenex. Stock/Shareholder; Self; Physiogenex. M. Shinohara: None. E. Brousseau: Employee; Self; Physiogenex. Y. Kageyama: None. T. Sulpice: Employee; Self; Physiogenex. Stock/Shareholder; Self; Physiogenex.