SSBP1 drives high fructose-induced glomerular podocyte ferroptosis via activating DNA-PK/p53 pathway
Wen-Yuan Wu,
Zi-Xuan Wang,
Tu-Shuai Li,
Xiao-Qin Ding,
Zhi-Hong Liu,
Jie Yang,
Lei Fang,
Ling-Dong Kong
Affiliations
Wen-Yuan Wu
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China
Zi-Xuan Wang
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China
Tu-Shuai Li
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China
Xiao-Qin Ding
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China
Zhi-Hong Liu
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China
Jie Yang
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China
Lei Fang
Jiangsu Key Laboratory of Molecular Medicine & Chemistry and Biomedicine Innovation Center, Medical School, Nanjing University, Nanjing, PR China; Corresponding author. Medical School of Nanjing University, Nanjing University, Nanjing, 210093, PR China.
Ling-Dong Kong
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China; Corresponding author. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, PR China.
High fructose consumption is a significant risking factor for glomerular podocyte injury. However, the causes of high fructose-induced glomerular podocyte injury are still unclear. In this study, we reported a novel mechanism by which high fructose induced ferroptosis, a newly form of programmed cell death, in glomerular podocyte injury. We performed quantitative proteomic analysis in glomeruli of high fructose-fed rats to identify key regulating proteins involved in glomerular injury, and found that mitochondrial single-strand DNA-binding protein 1 (SSBP1) was markedly upregulated. Depletion of SSBP1 could alleviate high fructose-induced ferroptotic cell death in podocytes. Subsequently, we found that SSBP1 positively regulated a transcription factor p53 by interacting with DNA-dependent protein kinase (DNA-PK) and p53 to drive ferroptosis in high fructose-induced podocyte injury. Mechanically, SSBP1 activated DNA-PK to induce p53 phosphorylation at serine 15 (S15) to promote the nuclear accumulation of p53, and thereby inhibited expression of ferroptosis regulator solute carrier family 7 member 11 (SLC7A11) in high fructose-exposed podocytes. Natural antioxidant pterostilbene was showed to downregulate SSBP1 and then inhibit DNA-PK/p53 pathway in its alleviation of high fructose-induced glomerular podocyte ferroptosis and injury. This study identified SSBP1 as a novel intervention target against high fructose-induced podocyte ferroptosis and suggested that the suppression of SSBP1 by pterostilbene may be a potential therapy for the treatment of podocyte ferroptosis in glomerular injury.
