title: TMEM16A exacerbates renal injury by activating P38/JNK signaling pathway to promote podocyte apoptosis in diabetic nephropathy mice.
abstract: 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. RT-PCR 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.
authors.affiliation: Department of Nephrology, Wuhan University, Zhongnan Hospital, No.169, Donghu Road, Wuchang District, Wuhan 430070, Hubei Province, PR China.
authors.forename: Huan
authors.initials: H
authors.lastname: Lian
authors.affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Nephrology, Wuhan University, Zhongnan Hospital, No.169, Donghu Road, Wuchang District, Wuhan 430070, Hubei Province, PR China. Electronic address: lianhuan11351@163.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D017209:Apoptosis; D018118:Chloride Channels / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels
keywords: Apoptosis; Diabetic nephropathy (DN); P38/JNK; Podocyte; TMEM16A