Department of Biochemistry, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea.
Department of Pharmacology, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea.
Int J Mol Sci. 2023 Sep 19;24(18):14295. doi: 10.3390/ijms241814295.
Renal ischemia-reperfusion (IR) causes acute kidney injury due to oxidative stress, tubular inflammation, and apoptosis. Early growth response 1 (Egr-1) is a transcription factor belonging to the immediate early gene family and is known to regulate cell proliferation, differentiation, and survival. Egr-1 expression is induced during renal IR; however, its pathogenic role and underlying mechanisms remain elusive. Here, we investigated the function of Egr-1 during renal IR using C57BL/6 mice and cultured renal proximal tubular HK-2 cells. Egr-1 expression increased immediately, 1-4 h after IR, whereas plasma creatinine and oxidative stress increased progressively over 24 h after IR. Egr-1 overexpression showed greater increases in plasma creatinine, renal tubular injury, and apoptosis than in the control after IR. Egr-1 overexpression also showed significant neutrophil infiltration and increased pro-inflammatory cytokines (TNF-α, MIP-2, and IL-6) after IR. Consistently, proximal tubular HK-2 cells showed immediate induction of Egr-1 at 1 h after hypoxia and reoxygenation, where its downstream target, p53, was also increased. Interestingly, Egr-1 overexpression enhanced p53 levels and tubular apoptosis, while the knockdown of Egr-1 reduced p53 levels and tubular apoptosis after HO treatment. Egr-1 was recruited to the p53 promoter, which activates p53 transcription, and Egr-1 induction occurred through Erk/JNK signaling kinases, as the specific inhibitors blocked its expression. Taken together, these results show that Egr-1 is upregulated in proximal tubular cells and contributes to renal IR injury by inducing tubular apoptosis, mediated by p53 transcriptional activation. Thus, Egr-1 could be a potential therapeutic target for renal IR injury.
肾缺血再灌注（IR）引起的氧化应激、肾小管炎症和细胞凋亡导致急性肾损伤。早期生长反应 1（Egr-1）是一种转录因子，属于即刻早期基因家族，已知其可调节细胞增殖、分化和存活。Egr-1 在肾 IR 时表达上调；然而，其致病作用及其潜在机制尚不清楚。在此，我们使用 C57BL/6 小鼠和培养的肾近端小管 HK-2 细胞研究了 Egr-1 在肾 IR 中的作用。Egr-1 表达在 IR 后 1-4 小时即刻增加，而血浆肌酐和氧化应激在 IR 后 24 小时内逐渐增加。Egr-1 过表达显示在 IR 后，血浆肌酐、肾小管损伤和细胞凋亡增加幅度大于对照组。Egr-1 过表达还显示在 IR 后明显的中性粒细胞浸润和促炎细胞因子（TNF-α、MIP-2 和 IL-6）增加。一致地，HK-2 细胞在缺氧和复氧后 1 小时即刻诱导 Egr-1，其下游靶标 p53 也增加。有趣的是，Egr-1 过表达增强了 p53 水平和肾小管凋亡，而在 HO 处理后 Egr-1 的敲低降低了 p53 水平和肾小管凋亡。Egr-1 被募集到 p53 启动子，激活 p53 转录，Egr-1 的诱导通过 Erk/JNK 信号激酶发生，因为特异性抑制剂阻断了其表达。总之，这些结果表明 Egr-1 在近端小管细胞中上调，并通过诱导肾小管凋亡，介导 p53 转录激活，导致肾 IR 损伤。因此，Egr-1 可能是肾 IR 损伤的潜在治疗靶点。
