Mitigation of renal inflammation and endoplasmic reticulum stress by vildagliptin and statins in high-fat high-fructose diet-induced insulin resistance and renal injury in rats

Abstract

Dyslipidemia and insulin resistance in obesity can lead to lipotoxicity and cellular damage. Renal lipotoxicity in association with an impairment of lipid metabolism induces renal damage through the activation of inflammation, ER stress, fibrosis and apoptosis. We investigated the effects of a combination treatment of the DPP-4 inhibitor vildagliptin and atorvastatin on renal lipotoxicity related to renal dysfunction and injury in a high-fat high-fructose diet (HFF)-induced insulin resistant condition. Male Wistar rats were fed on a high-fat diet and were given drinking water with 10% fructose for 16 weeks. After that, rats were divided into: no treatment (HFF), treatment with vildagliptin, atorvastatin and vildagliptin plus atorvastatin for 4 weeks. The results demonstrated that the combination treatment prominently improved insulin resistance, dyslipidemia and kidney morphological changes induced by HFF. These changes correlated well with the increased expression of nephrin and podocin and decreased urine protein. Notably, the combined treatment produced greater improvement in renal lipid metabolism through increasing fatty acid oxidation with the decreases in fatty acid transporters and fatty acid synthesis, thereby reducing renal lipid accumulation in HFF rats. The reduction in renal lipotoxicity via diminishing renal inflammation, ER stress, fibrosis and apoptosis was also more significant in the combined treatment group than in the other groups in which the drug was used as a monotherapy. In conclusion, the combination therapy produced synergistic beneficial effects on metabolic parameters, lipid metabolism and accumulation related to renal lipid accumulation-induced lipotoxicity and kidney injury in the HFF-induced insulin resistant model with improved outcomes.