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

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-03-04 DOI:10.1038/s41401-025-01498-7
Ting-Ting Yang, Yu-Ting Shao, Qian Cheng, Yu-Tian He, Zhen Qiu, Dan-Dan Pan, Huan-Ming Zhang, Zhen-Zhou Jiang, Meng Yan, Chang-Jiang Ying, Bao-Jing Li, Jun-Jie Liu, Si-Tong Qian, Tao Wang, Xiao-Xing Yin, Qian Lu
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引用次数: 0

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.

YY1/HIF-1α/mROS正反馈回路促进小鼠早期糖尿病肾病肾小球系膜细胞增殖
系膜细胞(MCs)是肾小球内最活跃的细胞。MCs在糖尿病肾病(DKD)早期过度增殖,最终导致肾小球硬化甚至肾功能衰竭;抑制早期DKD肾小球MC增殖是一种很有希望的早期DKD预防和治疗策略。我们前期的研究表明,锌指蛋白阴阳1 (YY1)是dkd诱导的肾纤维化的一种新的调节因子。在本研究中,我们研究了YY1在DKD患者肾小球MC增殖中的作用。我们首先发现YY1在DKD患者和db/db小鼠的肾小球MCs以及高糖(HG)处理的SV40-MES13细胞中的表达水平显著升高。通过使用YY1表达/敲低质粒,我们证实YY1对体外肾小球MC增殖有促进作用。我们发现YY1上调hg处理的SV40-MES13细胞中缺氧诱导因子-1α (HIF-1α)的表达和活性,导致mROS过量产生。此外,mROS参与了YY1/HIF-1α信号的正反馈调节,YY1/HIF-1α/mROS正反馈回路加剧了hg处理的SV40-MES13细胞肾小球MC的增殖。此外,肾特异性YY1过表达促进正常小鼠肾小球MC增殖,而肾特异性YY1敲低通过灭活HIF-1α/ROS信号通路,减轻早期糖尿病小鼠肾小球MC增殖。总之,YY1/HIF-1α/mROS正反馈回路可能是克服早期DKD肾小球硬化的一个有吸引力的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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