NR5A2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting MMP25 transcription

Abstract Epithelial-to-mesenchymal transition (EMT) is crucial for the progression of renal tubulointerstitial fibrosis, typically leading to end-stage renal failure. The role of Nuclear receptor subfamily 5 group A member 2 (NR5A2) in renal fibrosis is not yet fully understood. This research assessed NR5A2 expression in human renal fibrosis and in mouse models with unilateral ureteral obstruction (UUO). We further investigated NR5A2's function in TGF-β1-driven renal tubular EMT. Our findings demonstrated a significant elevation in NR5A2 and profibrogenic agents like collagen-I(Col-Ⅰ), alpha-smooth muscle actin (α-SMA), and fibronectin (FN) in the UUO-induced renal fibrosis mouse model. Suppressing NR5A2 and blocking it with ML180 diminished the TGF-β1-induced expression of E-cadherin, α-SMA, Col-Ⅰ , and FN in HK2 cells. Functionally, NR5A2 boosted MMP25 expression in HK2 cells after TGF-β1 activation. Luciferase and Chromatin Immunoprecipitation (ChIP) assays verified NR5A2's attachment to a distinct motif on the MMP25 promoter, initiating transcription. Crucially, silencing MMP25 countered the NR5A2-induced elevation of profibrogenic factors in HK2 cells following TGF-β1 activation. These insights reveal that NR5A2 orchestrates TGF-β1-prompted EMT in renal tubular cells via MMP25, highlighting a novel avenue for curbing renal fibrosis.