Tubular FoxP2 and Kidney Fibrosis

Abstract

Key Points:

1. FOXP2/Foxp2 is overexpressed in human and in murine unilateral ureteral obstruction and unilateral ischemia-reperfusion models.

2. Foxp2 overexpression mediates epithelial-to-mesenchymal transition and G2/M cell cycle arrest in kidney tubular cells to promote fibrosis.

Background: 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 (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 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.

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 UUO and UIRI 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 through Smad3 signaling while knockdown of Foxp2 suppressed TGF-β-induced EMT 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 phosphatidylinositol 3-kinase/protein kinase B 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 EMT 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 EMT and cell cycle arrest in kidney tubules, contributing to the progression of CKD.