The chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays essential roles in organogenesis of embryos. Recently COUP-TFII is also implicated in several diseases in adults. Here we focus on the role of COUP-TFII in cisplatin-induced acute kidney injury (AKI). COUP-TFII was the most abundantly expressed in the kidney among organs. Male tamoxifen-inducible COUP-TFII-knockout mice or control mice were intraperitoneally treated with 30 mg/kg body weight of cisplatin at 12 weeks old to induce AKI. The kidney samples were subject to morphological studies, terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling (TUNEL) assay, immunohistochemistry and RT-qPCR. Serum levels of creatinine, blood urea nitrogen (BUN) and tumor necrosis factor alpha (TNF-α) were measured. Administration of cisplatin induced a more severe AKI in adult COUP-TFII-knockout mice. An increase in dead cells in both the proximal tubules and thick ascending limb of Henle's loop (TAL) was observed in the knockout mouse kidney. The expression levels of COUP-TFII decreased in the TAL by cisplatin administration. There was no difference in the expression levels of transporter mRNAs responsible for cellular cisplatin uptake between control and knockout mouse kidney. COUP-TFII-knockout mice and COUP-TFII-depleted cells exhibited an elevation in TNF-α levels, suggesting the involvement of the TNF-α pathway. Chromatin immunoprecipitation showed that COUP-TFII was enriched in the potential binding site, suggesting that COUP-TFII might directly suppress the TNF-α gene at transcriptional level. These results indicate the involvement of COUP-TFII in the pathophysiology of AKI and COUP-TFII may be a potential therapeutic target for AKI.
Keywords: Acute kidney injury (AKI); Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII); Cisplatin; Nuclear receptor; Tumor necrosis factor alfa (TNF-α).