Tubular FoxP2 and Kidney Fibrosis

Background: Kidney fibrosis is the final common pathway of progressive chronic kidney disease (CKD) that leads to kidney failure, for which there are limited 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.

Methods: Human kidney biopsies were used to assess Foxp2 expression. Tubule-specific Foxp2 knockout mice were generated through LoxP-Cre transgenic manipulation and applied to murine models progressive CKD, including unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI). Cultured kidney tubular epithelial cells were used to analyse the underlying cellular mechanisms.

Results: Foxp2 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 unilateral ureteral obstruction and unilateral ischemic-reperfusion models that recapitulate progressive CKD, tubule-specific deletion of Foxp2 attenuated kidney inflammation and tubulointerstitial fibrosis, accompanied by reduction in cell cycle arrest. In mouse tubular epithelial cells, TGF-β upregulated Foxp2 expression via Smad3 signaling while knockdown of Foxp2 suppressed TGF-β-induced epithelial-to-mesenchymal transition and accumulation of extracellular matrix proteins. 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-β signaling pathways, and further revealed that Foxp2 directly regulated the transcriptional activities of collagen-1, E-cadherin and p21 that are involved in epithelial-to-mesenchymal transition and cell cycle arrest, thereby promoting the profibrotic process.

Conclusions: Our findings demonstrate a novel role of Foxp2 in promoting kidney fibrosis in murine UUO and UIRI by activating epithelial-to-mesenchymal transition and cell cycle arrest in kidney tubules, contributing to the progression of CKD.