Lethal (3) malignant brain tumor-like 2 (L3MBTL2) protein protects against kidney injury by inhibiting the DNA damage-p53-apoptosis pathway in renal tubular cells.
机构:[1]Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese Universityof Hong Kong, Hong Kong, China[2]Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan,China[3]Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, HongKong, China[4]Department of Nephrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China深圳市康宁医院深圳医学信息中心中国医学科学院阜外医院深圳医院[5]The KeyLaboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China
DNA damage contributes to renal tubular cell death during kidney injury, but how DNA damage in tubular cells is regulated is not fully understood. Lethal (3) malignant brain tumor-like 2 (L3MBTL2), a novel polycomb group protein, has been implicated in regulating chromatin architecture. However, the biological functions of L3MBTL2 are largely undefined. Here we found that L3MBTL2 was expressed in the nuclei of renal tubular epithelial cells in mice. Ablation of L3mbtl2 in renal tubular cells resulted in increases in nuclear DNA damage, p53 activation, apoptosis, tubular injury and kidney dysfunction after cisplatin treatment or unilateral ureteral obstruction. In vitro, inhibition of L3MBTL2 sequentially promoted histone γH2AX expression, p53 activation and apoptosis in cisplatin-treated mouse proximal tubular TKPTS cells. Inhibition of p53 activity attenuated the apoptosis induced by L3mbtl2 deficiency after cisplatin treatment both in vivo and in vitro. Intriguingly, unlike other polycomb proteins, L3MBTL2 was not recruited to DNA damage sites, but instead increased nuclear chromatin density and reduced initial DNA damage load. Thus, L3MBTL2 plays a protective role in kidney injury, in part by inhibiting the DNA damage-p53-apoptosis pathway.
基金:
This study was supported by the startup fund offered by The Chinese University of Hong Kong (CUHK; to YX), RGC-NSFC joint grant N_CUHK432/12 (to YX), CUHK direct grants 4054217 and 4054137 (to YX), National Science Foundation of China grant 913391179 (to YH),and General Research Fund grants 478812, 14102214, and14104614 (to BF).
第一作者机构:[1]Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese Universityof Hong Kong, Hong Kong, China
通讯作者:
通讯机构:[1]Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese Universityof Hong Kong, Hong Kong, China[5]The KeyLaboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China[*1]School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong[*2]Model Animal Research Center, 12 Xuefu Rd, Pukou High-Tec District, Nanjing 210061, China
推荐引用方式(GB/T 7714):
Huihui Huang,Chunhua Xu,Yang Wang,et al.Lethal (3) malignant brain tumor-like 2 (L3MBTL2) protein protects against kidney injury by inhibiting the DNA damage-p53-apoptosis pathway in renal tubular cells.[J].KIDNEY INTERNATIONAL.2018,93(4):855-870.doi:10.1016/j.kint.2017.09.030.
APA:
Huihui Huang,Chunhua Xu,Yang Wang,Chenling Meng,Wenjing Liu...&Yin Xia.(2018).Lethal (3) malignant brain tumor-like 2 (L3MBTL2) protein protects against kidney injury by inhibiting the DNA damage-p53-apoptosis pathway in renal tubular cells..KIDNEY INTERNATIONAL,93,(4)
MLA:
Huihui Huang,et al."Lethal (3) malignant brain tumor-like 2 (L3MBTL2) protein protects against kidney injury by inhibiting the DNA damage-p53-apoptosis pathway in renal tubular cells.".KIDNEY INTERNATIONAL 93..4(2018):855-870