L3MBTL2 protein protects against kidney injury by inhibiting the DNA damage-p53-apoptosis pathway in renal tubular cells
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AbstractIntroduction and aims: 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. In this study, we aim to define its role in adult kidney.
Methods: We generated tubular epithelial cell conditional L3mbtl2 knockout (L3mbtl2 cKO) mice. L3mbtl2 cKO mice and their wide type (WT) littermates were subjected to intraperitoneal injection of cisplatin or unilateral ureteral obstruction (UUO) to induce kidney injury. Mouse proximal tubular TKPTS cells were used for mechanistic studies.
Results: We found that L3MBTL2 was expressed in the nuclei of renal tubular epithelial cells in mice. L3mbtl2 cKO mice exhibited normal phenotypes compared with WT mice under basal conditions. During kidney injury, a protective role of L3MBTL2 was manifested. Specifically, the kidneys of L3mbtl2 cKO mice were much more injured than those of WT mice after cisplatin treatment or UUO, as they showed increases in nuclear DNA damage, p53 activation, apoptosis, tubular injury and kidney dysfunction. In vitro, inhibition of L3MBTL2 sequentially promoted histone γH2AX expression, p53 activation and apoptosis in mouse proximal tubular TKPTS cells after cisplatin treatment. Inhibition of p53 activity attenuated the apoptosis induced by L3mbtl2 deficiency after cisplatin treatment both in vivo and in vitro. Intriguingly, we found L3MBTL2 was not recruited to DNA damage sites, but instead increased nuclear chromatin density and reduced initial DNA damage load.
Conclusion: L3MBTL2 plays a protective role in kidney injury, in part by inhibiting the DNA damage-p53-apoptosis pathway.
All Author(s) ListHuihui HUANG, Chunhua XU, Yang WANG, Chenling MENG, Wenjing LIU, Yueshui ZHAO, Xiao-Ru HUANG, Wenxing YOU, Bo FENG, Zhi-Hua ZHENG, Yu HUANG, Hui-Yao LAN, Jinzhong QIN, Yin XIA
Name of Conference55th ERA-EDTA Congress
Start Date of Conference25/05/2018
End Date of Conference27/05/2018
Place of ConferenceCopenhagen
Country/Region of ConferenceDenmark
Year2018
LanguagesEnglish-United States

Last updated on 2018-25-06 at 10:38