2. Academic Validation
  3. YY1 was indispensable for the alleviation of quercetin on diabetic nephropathy-associated tubulointerstitial inflammation

YY1 was indispensable for the alleviation of quercetin on diabetic nephropathy-associated tubulointerstitial inflammation

  • Phytomedicine. 2023 Jan 11;111:154659. doi: 10.1016/j.phymed.2023.154659.
Tingting Yang 1,  Yinlu Hu 2,  Wenjie Jiang 1,  Jiale Pang 1,  Yequan Zhou 1,  Huanming Zhang 1,  Zeyuan Yin 3,  Zhenzhou Jiang 4,  Sitong Qian 1,  Chujing Wei 4,  Meng Yan 1,  Xia Zhu 1,  Tao Wang 5,  Qian Lu 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
  • 2 Department of Pharmacy, Wuxi Higher Health Vocational Technology School, Wuxi 214000, China.
  • 3 Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom.
  • 4 New drug screening center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
  • 5 Department of Pharmacy, The affiliated hospital of Xuzhou Medical University, Xuzhou 221006, China.
  • 6 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China. Electronic address: [email protected].
PMID: 36641979 DOI: 10.1016/j.phymed.2023.154659
Abstract

Background: The emergence of tubulointerstitial inflammation (TI) could accelerate the development of tubulointerstitial fibrosis (TIF) of diabetic nephropathy (DN). Yin Yang 1 (YY1) was a new pro-inflammatory mediator and became the important target of DN-related TIF. Quercetin performed an effective role in anti-inflammation and was probable to bind to YY1. However, the role of YY1 in quercetin's anti-inflammatory effect on DN-related TIF was uncovered.

Purpose: To investigate the potential effect and mechanism of quercetin against DN-related TI.

Study design and methods: The protein levels of YY1 were examined in the renal tubular epithelial cells (RTECs) of db/db mice and HG-cultured HK-2 cells. Molecular modeling studies and YY1 overexpression lentivirus vector were selected to further confirm the indispensable part of YY1 in quercetin's TI protection in vitro. Luciferase assay and chromatin immunoprecipitation (ChIP) assay were carried out to identify whether YY1 directly regulated IL-6/STAT3 signaling by binding to the IL-6 promoter in quercetin's TI protection in vitro. At last, the important role of YY1-mediated IL-6/STAT3 signaling in quercetin's TIF protection effect was further identified by using of YY1 overexpression lentivirus vector and IL-6 specific inhibitor tocilizumab.

Results: Along with the alleviated tubulointerstitial injury by quercetin in the RTECs of db/db mice and HK-2 cells stimulated by HG, YY1-mediated IL-6/STAT-3 pathway involved in TI protection of quercetin in vivo and in vitro. Quercetin bound to YY1 and decreased its protein expression, and YY1 directly suppressed IL-6 transcription by bounding to its promoter, resulting in the alleviation of inflammation by inactivating of IL-6/STAT-3 pathway in vitro. YY1-mediated IL-6/STAT-3 pathway was also indispensable for the alleviation of quercetin on DN-associated TIF.

Conclusion: YY1 could not be absent from quercetin's anti-inflammatory effect on DN-associated TIF via alleviating IL-6/STAT-3 pathway mediated TI.

Keywords

Diabetic nephropathy; IL-6/STAT-3 pathway; Quercetin; Tubulointerstitial inflammation; YY1.

Figures
Products