Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. While clinical therapies improve the quality of life of diabetic patients with DN, they only slow the rate of progression and therefore novel therapies are required. The study of the Glucagon-like peptide (GLP)-1 pathway is of current clinical interest as demonstrated by the number of clinical trials targeting GLP-1. The role of the GLP-1 axis in DN is not clearly understood. Therefore, the aim of this study was to explore the GLP-1 axis in DN and its interaction with the receptor for advanced glycation end products (RAGE), central in renal fibrosis and inflammation.
Methods: Primary mesangial cells (MC) were isolated from C57BL/6 mice and treated AGE-modified BSA (AGE-BSA, RAGE ligand) (100µg/ml) or BSA control (24 h). Cells were concurrently treated with or without with the GLP-1 agonist, Exendin-4 (1nM). Cell surface expression of RAGE and GLP-1 receptor (GLP-1R) was analysed by flow cytometry. 8-week old C57BL/6 and RAGE (-/-) mice were rendered diabetic by low-dose streptozotocin. In addition, C57BL/6 control and diabetic mice were further randomised to receive Exendin-4 (2.5µg/kg), a GLP-1 agonist. All mice were followed for 24 weeks.
Results: Exposure of MCs to AGE-BSA resulted in an increase in cell surface expression of RAGE and a decrease in GLP-1R (p<0.05). By contrast, treatment of MCs with Exendin-4 prevented the AGE-mediated increase in RAGE expression and concomitantly upregulated GLP-1R (p<0.05). A decrease in circulating and renal GLP-1 was exhibited in diabetic wild type mice compared to control which was not seen in diabetic RAGE(-/-) mice (p<0.05). Treatment of diabetic mice with exendin-4 decreased albuminuria and renal RAGE expression compared to untreated diabetic C57Bl/6 mice (p<0.05).
Conclusions: These data demonstrate that targeting the GLP-1 pathway is renoprotective in the setting of DN, independent of blood glucose lowering and highlights an interaction between the RAGE and GLP-1 pathways. Further investigation of how GLP-1 regulates the RAGE pathway is warranted.