YY1/HIF-1α/mROS positive-feedback loop exacerbates glomerular mesangial cell proliferation in mouse early diabetic kidney disease.

Mesangial cells (MCs) are the most active intrinsic cells in the glomerulus. MCs excessively proliferate at the early stage of diabetic kidney disease (DKD), eventually causing glomerular sclerosis and even renal failure; inhibiting glomerular MC proliferation in early DKD is a promising prevention and treatment strategy for early DKD. Our previous study shows that Yin Yang 1 (YY1), a zinc finger protein, is a novel regulator of DKD-induced renal fibrosis. In this study we investigated the role of YY1 in glomerular MC proliferation in DKD in vivo and in vitro. We first showed that YY1 expression levels were significantly increased in the glomerular MCs of DKD patients and db/db mice and in high glucose (HG)-treated SV40-MES13 cells. By using YY1 expression/knockdown plasmids, we confirmed that YY1 contributed to glomerular MC proliferation in vitro. We demonstrated that YY1 upregulated hypoxia-inducible factor-1 alpha (HIF-1α) expression and activity in HG-treated SV40-MES13 cells, leading to overproduction of mROS. Moreover, mROS contributed to positive feedback regulation of YY1/HIF-1α signaling, and the YY1/HIF-1α/mROS positive feedback loop exacerbated glomerular MC proliferation in HG-treated SV40-MES13 cells. In addition, renal-specific YY1 overexpression promoted glomerular MC proliferation in normal mice, whereas renal-specific YY1 knockdown mitigated MC proliferation in early diabetic mice by inactivating HIF-1α/ROS signaling. In conclusion, the YY1/HIF-1α/mROS positive feedback loop might be an attractive therapeutic target for overcoming glomerulosclerosis in early DKD.