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  • Title: Knockout of Zeb2 ameliorates progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia-reperfusion injury.
    Author: Inotani S, Taniguchi Y, Nakamura K, Nishikawa H, Matsumoto T, Horino T, Fujimoto S, Sano S, Yanagita M, Terada Y.
    Journal: Nephrol Dial Transplant; 2022 Feb 25; 37(3):454-468. PubMed ID: 34724064.
    Abstract:
    BACKGROUND: Zeb2, a zinc finger E-box-binding homeobox transcription factor, regulates transforming growth factor (TGF)-β signaling pathway. However, its role in the pathogenesis of acute kidney injury (AKI) and AKI-to-chronic kidney disease (CKD) transition is unclear. METHODS: We evaluated Zeb2 function in a bilateral renal ischemia-reperfusion injury (IRI)-induced AKI model using proximal tubule-specific Zeb2 conditional knockout (Zeb2-cKO) and wild-type (WT) mice, and in renal biopsy samples. RESULTS: In Zeb2-cKO mice, the levels of plasma creatinine and blood urea nitrogen post-IRI were significantly lower than that in WT mice. Immunohistological analysis revealed mild tubular injury, reduced neutrophil infiltration, fewer fibrotic changes and reduced expression of fibrotic proteins [collagen type IV, α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF)], at 3-14 days post-IRI. Zeb2 expression was upregulated in proximal tubular cells post-IRI in WT mice. Zeb2 siRNA transfection reduced TGF-β-stimulated mRNA and protein expression of collagen type IV, α-SMA, fibronectin and CTGF in cultured renal tubular cells. Patients with AKI-to-CKD transition exhibited high Zeb2 expression in renal tubules, as revealed by renal biopsy. Hypoxia and CoCl2-treatment upregulated Zeb2 promoter activity and mRNA and protein expression in cultured renal tubular epithelial cells, suggesting a regulatory role for hypoxia. CONCLUSIONS: Zeb2 was upregulated in renal tissues in both mice and humans with AKI. Zeb2 regulates fibrotic pathways in the pathogenesis of AKI and AKI-to-CKD transition. Therefore, inhibition of Zeb2 could be a potential therapeutic strategy for AKI.
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