STIM promotes the epithelial-mesenchymal transition of podocytes through regulation of FcγRII activity in diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication in diabetic patients and has been considered as the main cause of end-stage renal disease. However, there are no studies on the role of stromal interaction molecule (STIM) and its two subtypes, STIM1 and STIM2, in the epithelial-to-mesenchymal transition (EMT) of podocytes induced by diabetic kidney disease (DKD). The present study suggests for the first time that STIM inhibition decreases DKD-induced EMT.All DKD patients were diagnosed based on renal biopsies carried out at the Department of Nephrology, Zhejiang Provincial People's Hospital and selected using the Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN. Images were taken and the number of positive puncta in cells was analyzed using software equipped for immunofluorescence microscopy. STIM1, STIM2, FcγRIIa, FcγRIIb, Nephrin, CTGF, and α-SMA protein levels were detected by Western blotting analysis using the corresponding antibodies. The viability of cells was measured using CCK-8 assays. Absorbance at 450 nm was measured with a Multiskan FC Microplate Reader (Thermo Scientific, USA) and the results were normalized to those of untreated cells. All statistical analyses were performed using SPSS 19.0 software (Stanford University, Stanford, CA, USA).A total of 30 DKD patients and 30 control patients were enrolled in the study. We found that the level of urine protein in patients and db/db diabetic mice is higher than control group and the levels of STIM1 and 2 significantly increased in DKD groups. We also demonstrated that STIM is upregulated during DKD injury. Next, we discovered that DKD-induced podocyte EMT is related to STIM overexpression in vivo and in vitro. Further research demonstrated that STIM siRNA reverses podocytes from DKD-induced injury and EMT and reverses FcγRII activity in HG-treated podocytes.Our study suggests that STIM and FcγRII play an essential role in the regulation of DKD-induced podocyte EMT. STIM is an essential component of FcγR activation and inhibition of STIM-mediated signaling pathway might be a new strategy to treat IgG-dependent renal diseases.