肾脏老化可能导致纤维化和功能障碍,然而潜在的机制仍不清楚.我们探讨了Polycomb蛋白Bmi1的缺乏是否通过DNA损伤反应(DDR)激活导致肾脏衰老,诱导肾小管上皮细胞(RTEC)衰老和上皮间质转化(EMT)。Bmi1基因敲除小鼠表现出氧化应激,DDR激活,RTEC衰老,衰老相关分泌表型(SASP),和年龄相关的肾脏纤维化。Bmi1缺乏损害肾脏结构和功能,增加血清肌酐/尿素,降低肌酐清除率,减少皮质厚度和肾小球数量。然而,丝氨酸-苏氨酸激酶Chk2的敲除减轻了这些衰老表型。转录组学鉴定了Bmi1缺陷型RTECs中转化生长因子β1(TGFβ1)的上调,但TGFβ1在Chk2敲除后下调。肿瘤抑制蛋白p53转录激活TGFβ1,促进RTECs中的EMT。Bmi1敲除或氧化应激(H2O2诱导)增加TGFβ1表达,和EMT在RTEC中,并被p53抑制部分逆转。一起,Bmi1缺乏导致氧化应激和DDR介导的RTEC衰老/SASP,从而激活p53和TGFβ1诱导EMT和年龄相关的纤维化。然而,阻断DDR(通过Chk2敲除)或p53改善这些变化。我们的研究揭示了Bmi1通过抑制DDR和p53/TGFβ1介导的EMT在衰老过程中保留肾脏结构和功能的机制。这些途径代表了检测和减弱年龄相关的肾脏衰退的潜在目标。
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.