COUP-TFII promotes macrophage-myofibroblast transition by attenuating HIF-1α-mediated glycolysis

Diabetic kidney disease (DKD) is among the most common complications of type 2 diabetes and severely affects patients' health and life. Renal fibrosis is an unavoidable pathway in the progression of DKD. Previous studies have shown that COUP-TFII is upregulated in DKD, but its regulatory mechanisms remain unclear.

Macrophages were treated with TGF-β. The expression levels of COUP-TFII, α-SMA, Col-I, HIF-1α, HK2, and PKM2 proteins were detected via Western blotting. Single-cell sequencing data and the GEO database were used. COUP-TFII knockdown vectors were constructed. The 22-week-old DB/DB DKD mice models were used, and the protein levels in renal tissues were analysed via immunofluorescence.

With TGF-β intervention, the protein expression levels of α-SMA and Col-I increased, and the COUP-TFII protein increased in macrophages. Following COUP-TFII knockdown, there was a notable decrease in the protein levels of α-SMA and Col-I. Conversely, the protein expression levels of HIF-1α, HK2, and PKM2 significantly increased. In the renal tissues of the DB/DB DKD mice, the expression levels of COUP-TFII were significantly increased.

TGF-β promotes Macrophage-Myofibroblast Transition (MMT) in DKD fibrosis by upregulating COUP-TFII, which suppresses HIF-1α-dependent glycolysis and subsequently elevates the expression of α-SMA and Col-I, driving DKD fibrosis progression.