2. Academic Validation
  3. Transient receptor potential channel 6 knockdown prevents apoptosis of renal tubular epithelial cells upon oxidative stress via autophagy activation

Transient receptor potential channel 6 knockdown prevents apoptosis of renal tubular epithelial cells upon oxidative stress via autophagy activation

  • Cell Death Dis. 2018 Oct 3;9(10):1015. doi: 10.1038/s41419-018-1052-5.
Xin Hou 1 2,  Haitao Xiao 1 3,  Yanhong Zhang 1 3,  Xixi Zeng 1 3,  Mengjun Huang 1 3,  Xiaoyun Chen 4,  Lutz Birnbaumer 5 6,  Yanhong Liao 7 8
Affiliations

Affiliations

  • 1 Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
  • 2 Department of Anatomy, Medical College, Affiliated Hospital, Hebei University of Engineering, 056002, Handan, China.
  • 3 Key Laboratory of Neurological Diseases of Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
  • 4 Department of Pathology, First Hospital of Wuhan, 430030, Wuhan, China.
  • 5 Institute of Biomedical Research (BIOMED), Catholic University of Argentina, C1107AFF, Buenos Aires, Argentina. birnbau1@gmail.com.
  • 6 Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA. birnbau1@gmail.com.
  • 7 Department of Anatomy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China. yhliao1@hust.edu.cn.
  • 8 Key Laboratory of Neurological Diseases of Ministry of Education, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China. yhliao1@hust.edu.cn.
PMID: 30282964 DOI: 10.1038/s41419-018-1052-5
Abstract

Reactive Oxygen Species (ROS) are generated under various pathological conditions such as renal ischemia/reperfusion (I/R) injury and provoke damage to multiple cellular organelles and processes. Overproduction of ROS causes oxidative stress and contributes to damages of renal proximal tubular cells (PTC), which are the main cause of the pathogenesis of renal I/R injury. Autophagy is a dynamic process that removes long-lived proteins and damaged organelles via lysosome-mediated degradation, which has an antioxidant effect that relieves oxidative stress. The canonical transient receptor potential channel 6 (TRPC6), a nonselective cation channel that allows passage of CA2+, plays an important role in renal disease. Yet, the relationship between TRPC6 and Autophagy, as well as their functions in renal oxidative stress injury, remains unclear. In this study, we found that oxidative stress triggered TRPC6-dependent CA2+ influx in PTC to inhibit Autophagy, thereby rendering cells more susceptible to death. We also demonstrated that TRPC6 knockout (TRPC6-/-) or inhibition by SAR7334, a TRPC6-selective inhibitor, increased autophagic flux and mitigated oxidative stress-induced Apoptosis of PTC. The protective effects of TRPC6 ablation were prevented by Autophagy inhibitors Chloroquine and Bafilomycin A1. Moreover, this study also shows that TRPC6 blockage promotes autophagic flux via inhibiting the PI3K/Akt/mTOR and ERK1/2 signaling pathways. This is the first evidence showing that TRPC6-mediated CA2+ influx plays a novel role in suppressing cytoprotective Autophagy triggered by oxidative stress in PTC, and it may become a novel therapeutic target for the treatment of renal oxidative stress injury in the future.

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