Early Growth Response 1 Contributes to Renal IR Injury by Inducing Proximal Tubular Cell Apoptosis

Abstract

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 H2O2 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.