Dapagliflozin improves early diabetic nephropathy by downregulating PPP2R2A and CXCL12/S100A13 through ROS- dependent

Abstract Diabetic nephropathy (DN) is a common chronic complication of diabetes mellitus (DM), and dapagliflozin, a representative drug of sodium-glucose co-transport protein 2 inhibitors (SGLT2i), is a novel hypoglycemic agent for the treatment of type 2 diabetes mellitus (T2DM), which has been shown to reverse microalbuminuria in early type 2 diabetic nephropathy (T2DN), but the mechanism of action remains to be elucidated. In this study, five patients with early T2DN treated in our hospital from October 2020 to May 2021 were selected for the study and were treated with insulin combined with dapagliflozin to lower glucose, and the initial insulin treatment was named as DN group, and the addition of dapagliflozin was named as DN-DAPA group, and another five patients with a healthy physical examination at the same period were selected as the blank control group (NC group). Patients' morning urine samples were collected and processed using iTRAQ unlabeled quantitative proteomics technology. Bioinformatics analysis was performed to obtain 193 differentially expressed proteins. 91 expressions were up-regulated and 72 expressions were down-regulated in the DN group compared with the NC group, and 11 expressions were up-regulated and 26 expressions were down-regulated in the DN-DAPA group compared with the DN group. Five significantly co-expressed protein molecules were screened at P < 0.05 and [logFC] >1.5: SOD1, SLC25A6, S100A13, PPP2R2A, CXCL12. Therefore, these differential proteins are associated with early T2DN injury. Molecularly, dapagliflozin improves mitochondrial oxidative stress and reduces urinary microalbumin excretion in early T2DN patients by inhibiting PPP2R2A and CXCL12/ S100A13 pathways to reverse early T2DN.