Tubular Foxp2 promotes kidney fibrosis by regulating epithelial-mesenchymal transition and cell cycle arrest
Kidney fibrosis results in progressive loss of function, ultimately leading to kidney failure, for which there are limited effective therapeutic strategies. The transcription factor, Forkhead box P2 (Foxp2), 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 Foxp2 in kidney fibrosis. Expression of Foxp2 was upregulated in kidney tubules from both human chronic glomerulonephritides and animal models of chronic kidney disease. In vitro, Foxp2 was induced in tubular epithelial cells via TGF-ß/Smad3 signaling while knockdown of Foxp2 suppressed TGF-ß-induced EMT and accumulation of extracellular matrix proteins. In vivo, tubule-specific deletion of Foxp2 attenuated kidney inflammation and tubulointerstitial fibrosis in murine unilateral ureteral obstruction and unilateral ischemic-reperfusion models of progressive CKD, which were accompanied by reduction in cell cycle arrest. Mechanistically, overexpression of Foxp2 inhibited tubular cell proliferation with induction of G2/M cell cycle arrest. Using chromatin-immunoprecipitation sequencing, we identified Foxp2 target genes that are enriched in PI3K/Akt and TGF-ß signaling pathways, and further revealed that Foxp2 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. Collectively, our findings provide novel evidence that Foxp2 regulates TGF-ß-induced EMT and cell cycle arrest, the key signaling pathways of kidney fibrosis, and suggest that Foxp2 may be a potential therapeutic target for kidney fibrosis. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for Foxp2 in Foxp2 overexpressing murine tubular epithelial cell line (C1.1). Input samples collected before immunoprecipitation were used as control for analysis.