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

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

  • Acta Pharmacol Sin. 2025 Mar 4. doi: 10.1038/s41401-025-01498-7.
Ting-Ting Yang # 1,  Yu-Ting Shao # 1,  Qian Cheng # 1,  Yu-Tian He 1,  Zhen Qiu 1,  Dan-Dan Pan 1,  Huan-Ming Zhang 1,  Zhen-Zhou Jiang 2,  Meng Yan 1,  Chang-Jiang Ying 3,  Bao-Jing Li 4,  Jun-Jie Liu 5 6,  Si-Tong Qian 1,  Tao Wang 7 8,  Xiao-Xing Yin 9,  Qian Lu 10
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China.
  • 2 New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Department of Endocrinology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China.
  • 4 College of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
  • 5 The First Clinical Medical College, Xuzhou Medical University, Xuzhou, 221004, China.
  • 6 Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China.
  • 7 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. misswt2011@126.com.
  • 8 Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China. misswt2011@126.com.
  • 9 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. yinxx@xzhmu.edu.cn.
  • 10 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. luqian@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 40038466 DOI: 10.1038/s41401-025-01498-7
Abstract

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.

Keywords

HIF-1α/mROS signaling; YY1; diabetes kidney disease; mesangial cell proliferation; positive-feedback loop.

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