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Zona occludens-2 (ZO-2) is a protein present at the tight junction and nucleus of epithelial cells. ZO-2 represses the transcription of genes regulated by the Wnt/β-catenin pathway. This pathway plays a critical role in podocyte injury and proteinuria. Here, we analyze whether the overexpression of ZO-2 in the glomerulus, by hydrodynamics transfection, prevents podocyte injury mediated by the Wnt/β-catenin pathway in the mouse model of adriamycin (ADR) nephrosis. By immunofluorescence and immunogold electron microscopy, we show that ZO-2 is present in mice glomerulus, not at the slit diaphragms where nephrin concentrates, but in the cytoplasm and at processes of podocytes. Our results indicate that in the glomeruli of mice treated with ADR, ZO-2 overexpression increases the amount of phosphorylated β-catenin, inhibits the expression of the transcription factor snail, prevents nephrin and podocalyxin loss, reduces podocyte effacement and massive fusions, restrains proteinuria, and supports urea and creatinine clearance. These results suggest that ZO-2 could be a new target for the regulation of hyperactive Wnt/β-catenin signaling in proteinuric kidney diseases. [ABSTRACT FROM AUTHOR]