Transcription Factor Foxp2 Promotes TGF-β1-Induced Kidney Fibrosis in Obstructive Nephropathy

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Background: Forkhead Box P2 protein (Foxp2) is a transcription factor involved in multiple biological activities including organ development, tissue injury and tumor growth. Recent studies showed that Foxp2 regulates epithelial-mesenchymal transition (EMT) during tumorigenesis. Given that EMT is a crucial process in kidney fibrosis, we aim to investigate whether Foxp2 has a functional role in the progression of chronic kidney disease. Methods: Foxp2 expression was evaluated in cultured tubular epithelial cells (C1.1) treated with TGF-β1 (10ng/mL). Foxp2 was knocked down by siRNA prior to TGF-β1 stimulation. Tubule-specific Foxp2 knockout (Ksp-Foxp2 KO) mice and wild type control (WT) were generated by Cre-LoxP strategy and subjected to unilateral ureteral obstruction (UUO). Kidneys were collected at day 7 after UUO for the assessment of kidney fibrosis by real-time qPCR, Western blotting and immunohistochemical staining. Results: In C1.1 cells, FoxP2 expression was significantly induced by TGF-β1, which was partly inhibited by Smad3-specific inhibitor. Knocking down FoxP2 significantly suppressed the expression levels of TGF-β1-induced fibrotic markers collagen 1, PAI-1 and restored the loss of epithelial marker E-cadherin. In the UUO kidneys, TGF-β1 expression level was lower in Ksp-Foxp2 KO group compared to that of WT. Collagen deposition and expression of fibrosis markers fibronectin and PAI-1, and macrophage infiltration were greatly reduced in UUO kidneys from Foxp2 KO compared to WT group. Conclusions: Foxp2 promotes TGF-β1-induced EMT and fibrotic changes in obstructed kidneys and may become a novel therapeutic target for kidney fibrosis. Fundings: Research Grants Council of Hong Kong (General Research Fund, grant no.17108719) and Hong Kong Society of Nephrology/Hong Kong Kidney Foundation Research Grant 2020

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