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.
Keywords: Zeb2; acute kidney injury; cytokine; fibrosis; ischemia–reperfusion injury.
© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.