Combination therapy with Exendin-4 and islet transplantation as a synergistic treatment for diabetic nephropathy in rats.

OBJECTIVE: To explore the improvement and mechanism of combination therapy with Exendin-4 (Ex4) and islet transplantation (IT) on the rat model with diabetic nephropathy (DN). MAIN METHODS: The DN rat model was established by injecting streptozotocin (STZ), supplemented by high-fat and high-glucose feeding. Forty DN rats were assigned to four groups treated with saline, Ex4, IT, and Ex4 combined with IT, respectively, using the healthy rat as normal control. The glomerular filtration barrier (GFB) and renal functions were assessed via the histopathological examination and urinalysis, respectively. Then general indexes, renal fibrosis-related factors, CTGF, TGF-β1, and the anti-renal fibrosis factor, HGF, PI3K/Akt/MTOR signaling pathway-related factors were investigated via immunohistochemical staining and western blotting method. KEY FINDING: Body weight, blood glucose level, %HbAlc and other diabetes-related factors were all significantly decreased in combination therapy group compare to all other three DN rat groups. After combination or mono treatment of Ex4 and IT, the GFB structure of DN model rats were all obviously improved compared with saline-treated ones. The 24 h-urine proteins and thickness glomerular basilemma in combination group were obviously down-regulated. The pathological change of podocytes, oxidative stress-related factors, the expression levels of HGF, CTGF and TGF-β1 were all obviously improved in combination group. Furthermore, combined treatment also effectively improved the oxidative stress related indicators, and down-regulated PI3K/Akt/MTOR signaling pathway compare to saline or any mono treatment group. CONCLUSIONS: Combined Ex4 with IT exhibited promising improvement on DN via inhibiting oxidative stress, fibrosis and down-regulating the PI3K/Akt/MTOR signaling pathway in DN rats.