MYCT1 attenuates renal fibrosis and tubular injury in diabetic kidney disease
Xin Li,
Qiu-Ling Fan,
Tian-Kui Ma,
Cong Liu,
Hang Shi,
Yuan-Yuan Sun,
Yue Wang,
Dong-Xue Ding,
Ao Tang,
Yu Qin,
Qi Yang,
Hong Ding,
Hang-Yu Li,
Wei-Neng Fu
Affiliations
Xin Li
Department of Medical Genetics, China Medical University, Shenyang, China; Department of Nephrology, Fourth Hospital of China Medical University, Shenyang, China
Qiu-Ling Fan
Department of Nephrology, First Hospital of China Medical University, Shenyang, China; Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Tian-Kui Ma
Department of Nephrology, First Hospital of China Medical University, Shenyang, China
Cong Liu
Department of General Surgery, First Hospital of Harbin Medical University, Harbin, China
Hang Shi
Department of Intensive Care Unit, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
Yuan-Yuan Sun
Department of Medical Genetics, China Medical University, Shenyang, China
Yue Wang
Department of Medical Genetics, China Medical University, Shenyang, China
Dong-Xue Ding
Department of Medical Genetics, China Medical University, Shenyang, China
Ao Tang
Department of Medical Genetics, China Medical University, Shenyang, China
Yu Qin
Department of Nephrology, Fourth Hospital of China Medical University, Shenyang, China
Qi Yang
Department of Nephrology, Fourth Hospital of China Medical University, Shenyang, China
Hong Ding
Department of Nephrology, Fourth Hospital of China Medical University, Shenyang, China
Hang-Yu Li
Department of General Surgery, Fourth Hospital of China Medical University, Shenyang, China; Corresponding author
Wei-Neng Fu
Department of Medical Genetics, China Medical University, Shenyang, China; Corresponding author
Summary: Tubulointerstitial abnormalities contribute to the progression of diabetic kidney disease (DKD). However, the underlying mechanism of the pathobiology of tubulointerstitial disease is largely unknown. Here, we showed that MYCT1 expression was downregulated in in vitro and in vivo DKD models. Adeno-associated virus (AAV)-Myct1 significantly attenuated renal dysfunction and tubulointerstitial fibrosis in diabetic db/db mice and downregulated Sp1 transcription and TGF-β1/SMAD3 pathway activation. In human proximal tubular epithelial cells, high glucose-induced high expression of SP1 and TGF-β1/SMAD3 pathway activation as well as overaccumulation of extracellular matrix (ECM) were abrogated by MYCT1 overexpression. Mechanistically, the binding of VDR to the MYCT1 promoter was predicted and confirmed using dual-luciferase reporter and ChIP analysis. VDR transcriptionally upregulates MYCT1. Our data reveal MYCT1 as a new and potential therapeutic target in treating DKD.