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Int J Biol Sci 2024; 20(6):2008-2026. doi:10.7150/ijbs.93598 This issue Cite

Research Paper

Chk2 Modulates Bmi1-Deficiency-Induced Renal Aging and Fibrosis via Oxidative Stress, DNA Damage, and p53/TGFβ1-Induced Epithelial-Mesenchymal Transition

Jinhong Lu^1#, Weiwei Sun^1#, Boyang Liu¹, Jinge Zhang¹, Rong Wang¹, David Goltzman², Dengshun Miao^1✉

1. The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China.
2. Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada.
^# These authors contributed equally to this work.

✉ Corresponding author: Dengshun Miao, M.D., Ph.D., The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China. Tel & FAX: 011-86-25-8686-9377; E-mail: dsmiaoedu.cn. More

Abstract

Renal aging may lead to fibrosis and dysfunction, yet underlying mechanisms remain unclear. We explored whether deficiency of the Polycomb protein Bmi1 causes renal aging via DNA damage response (DDR) activation, inducing renal tubular epithelial cell (RTEC) senescence and epithelial-mesenchymal transition (EMT). Bmi1 knockout mice exhibited oxidative stress, DDR activation, RTEC senescence, senescence-associated secretory phenotype (SASP), and age-related fibrosis in kidneys. Bmi1 deficiency impaired renal structure and function, increasing serum creatinine/urea, reducing creatinine clearance, and decreasing cortical thickness and glomerular number. However, knockout of the serine-threonine kinase Chk2 alleviated these aging phenotypes. Transcriptomics identified transforming growth factor beta 1 (TGFβ1) upregulation in Bmi1-deficient RTECs, but TGFβ1 was downregulated upon Chk2 knockout. The tumor suppressor protein p53 transcriptionally activated TGFβ1, promoting EMT in RTECs. Bmi1 knockout or oxidative stress (induced with H₂O₂) increased TGFβ1 expression, and EMT in RTECs and was partly reversed by p53 inhibition. Together, Bmi1 deficiency causes oxidative stress and DDR-mediated RTEC senescence/SASP, thus activating p53 and TGFβ1 to induce EMT and age-related fibrosis. However, blocking DDR (via Chk2 knockout) or p53 ameliorates these changes. Our study reveals mechanisms whereby Bmi1 preserves renal structure and function during aging by suppressing DDR and p53/TGFβ1-mediated EMT. These pathways represent potential targets for detecting and attenuating age-related renal decline.

Keywords: Bmi1, Chk2, aging-related renal fibrosis, p53, TGFβ1

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