Tubular FoxP2 and Kidney Fibrosis.

Abstract

<i>FOXP2/Foxp2</i> is overexpressed in human and in murine unilateral ureteral obstruction and unilateral ischemia-reperfusion models. <i>Foxp2</i> overexpression mediates epithelial-to-mesenchymal transition and G2/M cell cycle arrest in kidney tubular cells to promote fibrosis. Kidney fibrosis is the final common pathway of progressive CKD that leads to kidney failure, for which there are limited therapeutic strategies. The transcription factor, Forkhead box P2 (<i>Foxp2</i>), has been implicated in organ development and tumorigenesis through its association with the epithelial-to-mesenchymal transition (EMT) process. In this study, we uncovered a novel role of <i>Foxp2</i> in kidney fibrosis. Human kidney biopsies were used to assess <i>FOXP2</i> expression. Tubule-specific <i>Foxp2</i> knockout mice were generated through LoxP-Cre transgenic manipulation and applied to murine models of progressive CKD, including unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI). Cultured kidney tubular epithelial cells were used to analyze the underlying cellular mechanisms. <i>FOXP2</i> expression was markedly increased in the tubular nuclei of human kidney biopsies of CKD from patients with IgA nephropathy, membranous nephropathy, and diabetic nephropathy. In murine UUO and UIRI models that recapitulate progressive CKD, tubule-specific deletion of <i>Foxp2</i> attenuated kidney inflammation and tubulointerstitial fibrosis, accompanied by reduction in cell cycle arrest. In mouse tubular epithelial cells, TGF-<i>β</i> upregulated <i>Foxp2</i> expression through Smad3 signaling while knockdown of <i>Foxp2</i> suppressed TGF-<i>β</i>-induced EMT and accumulation of extracellular matrix proteins. Mechanistically, overexpression of <i>Foxp2</i> inhibited tubular cell proliferation with induction of G2/M cell cycle arrest. Using chromatin-immunoprecipitation sequencing, we identified <i>Foxp2</i> target genes that are enriched in phosphatidylinositol 3-kinase/protein kinase B and TGF-<i>β</i> signaling pathways and further revealed that <i>Foxp2</i> directly regulated the transcriptional activities of collagen-1, E-cadherin, and p21 that are involved in EMT and cell cycle arrest, thereby promoting the profibrotic process. Our findings demonstrate a novel role of <i>Foxp2</i> in promoting kidney fibrosis in murine UUO and UIRI by activating EMT and cell cycle arrest in kidney tubules, contributing to the progression of CKD.