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  2. Inhibition of MyD88 attenuates angiotensin II-induced hypertensive kidney disease via regulating renal inflammation

Inhibition of MyD88 attenuates angiotensin II-induced hypertensive kidney disease via regulating renal inflammation

  • Int Immunopharmacol. 2022 Sep 15;112:109218. doi: 10.1016/j.intimp.2022.109218.
Ke Lin 1 Wu Luo 2 Na Yang 1 Lan Su 3 Hao Zhou 3 Xiang Hu 4 Yi Wang 5 Zia A Khan 6 Weijian Huang 3 Gaojun Wu 7 Guang Liang 8
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China; Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 3 Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 4 Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China.
  • 6 Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario N6A 5C1, Canada.
  • 7 Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wugaojun@wzhospital.cn.
  • 8 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China; Department of Cardiology and Medical Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325001, China. Electronic address: wzmcliangguang@163.com.
Abstract

Background: Kidney damage is a frequent event in the course of hypertension. Recent researches highlighted a critical role of non-hemodynamic activities of angiotensin II (Ang II) in hypertension-associated kidney fibrosis and inflammation. These activities are mediated through toll-like receptors (TLRs) but the mechanisms by which Ang II links TLRs to downstream inflammatory and fibrogenic responses is not fully known. In this study, we investigated the role of TLR adapter protein called myeloid differentiation primary-response protein-88 (MyD88) as the potential link.

Methods: C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop nephropathy. Mice were treated with small-molecule MyD88 Inhibitor LM8. In vitro, MyD88 was blocked using siRNA or LM8 in Ang II-challenged renal tubular epithelial cells.

Results: We show that MyD88 is mainly located in tubular epithelial cells and Ang II increases the interaction between TLR4 and MyD88. This interaction activates MAPKs and nuclear factor-κB (NF-κB), leading to increased production of inflammatory and fibrogenic factors. Inhibition of MyD88 by siRNA or selective inhibitor LM8 supresses MyD88-TLR4 interaction, NF-κB activation, and elaboration of inflammatory cytokines and fibrosis-associated factors. These protective actions resulted in decreased renal pathological changes and preserved renal function in LM8-treated hypertensive mice, without affecting hypertension.

Conclusion: These results demonstrate that Ang II induces inflammation and fibrosis in renal tubular epithelial cells through MyD88 and present MyD88 as a potential point of intervention for hypertension-associated kidney disease.

Keywords

Angiotensin II; Fibrosis; Hypertensive kidney disease; Inflammation; MyD88.

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