GLP-1 Receptor Agonist Improves Mitochondrial Energy Status and Attenuates Nephrotoxicity In Vivo and In Vitro

High-sugar and high-fat diets cause significant harm to health, especially via metabolic diseases. In this study, the protective effects of the antidiabetic drug exenatide (synthetic exendin-4), a glucagon-like peptide 1 (GLP-1) receptor agonist, on high-fat and high-glucose (HFHG)-induced renal injuries were investigated in vivo and in vitro. In vivo and in vitro renal injury models were established. Metabolomic analysis based on ¹H-nuclear magnetic resonance was performed to examine whether exenatide treatment exerts a protective effect against kidney injury in diabetic rats and to explore its potential molecular mechanism. In vivo, 8 weeks of exenatide treatment resulted in the regulation of most metabolites in the diabetes mellitus group. In vitro results showed that exendin-4 restored the mitochondrial functions of mesangial cells, which were perturbed by HFHG. The effects of exendin-4 included the improved antioxidant capacity of mesangial cells, increased the Bcl-2/Bax ratio, and reduced protein expression of cyt-c and caspase-3 activation. In addition, exendin-4 restored mesangial cell energy metabolism by increasing succinate dehydrogenase and phosphofructokinase activities and glucose consumption while inhibiting pyruvate dehydrogenase E1 activity. In conclusion, GLP-1 agonists improve renal injury in diabetic rats by ameliorating metabolic disorders. This mechanism could be partially related to mitochondrial functions and energy metabolism.