Diabetic nephropathy (DN) is one of the most common microvascular complication of diabetes mellitus (DM) as well as the main reason resulting in chronic renal failure. Transmembrane protein 16A (TMEM16A) plays an important role in multiple physiological actions. Here we found that it was up regulated in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) amplification, Western blot detection, Periodic Acid Schiff (PAS) staining and immunohistochemical analysis confirmed that TMEM16A deficiency alleviated renal injury in diabetic mice and TMEM16A knockout diabetic mice were protected from the HFD-induced reduction in Nephrin expression. To understand further the molecular mechanism of its function, podocytes treated with high glucose (HG, 30 mmol/L glucose) in vitro was chosen as a model to study its signal transduction pathway. Nephrin expression level in siRNA-TMEM16A group was significantly higher than that of the HG group (also called Model group). Flow cytometric analysis revealed that podocyte apoptosis in siRNA-TMEM16A group was significantly lower than that of the Model group. RTPCR and Western blot exhibited that apoptosis-related genes including apoptosis-inducing factor (AIF) and cystinylaspartate specific protease-3/-9 (caspase-3/-9) were dramatically down regulated in siRNA-TMEM16A group, compared with Model group. Phosphorylation levels of P38 and JNK in siRNA-TMEM16A group were lower than that of the Model group. Thus, TMEM16A is one of the critical components of a signal transduction pathway that links renal injury to podocyte apoptosis in DN. (C) 2017 Published by Elsevier Inc.