Metabolomics study of cadmium-induced diabetic nephropathy and protective effect of caffeic acid phenethyl ester using UPLC-Q-TOF-MS combined with pattern recognition

Diabetic nephropathy (DN) is the most severe complication of diabetes and multiple factors are involved in the pathogenesis of DN. Among them, cadmium (Cd) acts as a risk factor inducing the occurrence of DN. The present study focused on investigating the protective role of caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, against Cd-induced DN in mice based on ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS)and pattern recognition. Serum and urine biochemical indexes were detected and histopathological observation has been done to evaluate the damage of Cd on animals. Moreover, the global serum profiles of different groups were distinguished by UPLC-Q-TOF-MS and principal component analysis (PCA) were applied for group differentiation and marker selection. Moreover, the influence of Cd on the oxidative status in DN mice were also evaluated by assessing the parameters of oxidative stress, proinflainmatory cytokines and antioxidant competence. As shown in the scores plots, the distinct clustering among controls, DN and CAPE groups were observed, significant changes in serum levels of LysoPC(18:1(11Z)), 2,3-dinor-8-iso-PGF2a, PS(18:1(9Z)/18:1(9Z)), DG(17:0/22:4 (7Z,10Z, 13Z, 16Z)/0:0) and Arachidonic acid(AA) were noted and identified as potential biomarkers, the effect of CAPE reverted them back to near normalcy. Further, It was observed a significant improvement in lipid peroxides (LPO) and protein carbonyls (PCO) levels in Cd-induced DN kidneys along with a significant decline in superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) levels, however, CAPE relieved these changes. In conclusion, the study suggested that the pathogenesis of DN caused by Cd probably owes to the perturbations of lipid metabolism and AA metabolism; CAPE seems to be effective agent and may be related to its potent antioxidant, anti-inflammatory properties and action as an Nrf2 activator.