Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).
Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2-/-mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice. Similarly, in the presence of small molecule MD2 specific inhibitor L6H21 or siRNA-MD2, the Ang II-induced increases of pro-fibrotic and pro-inflammatory molecules were prevented in tubular NRK-52E cells. MD2 blockade also inhibited activation of NF-κB and ERK. Moreover, MD2 blockade prevented the Ang II-stimulated formation of the MD2/TLR4/MyD88 signaling complex, as well as the increased surface binding of Ang II in NRK-52E cells. In addition, Ang II directly bound recombinant MD2 protein, rather than TLR4 protein. We conclude that MD2 is a significant contributor in the Ang II-induced kidney inflammatory injury in chronic renal diseases. Furthermore, MD2 inhibition could be a new and important therapeutic strategy for preventing progression of chronic renal diseases.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Zheng
Z
Xu
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Weixin
W
Li
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.|The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Jibo
J
Han
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Chunpeng
C
Zou
The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Weijian
W
Huang
The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Weihui
W
Yu
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Xiaoou
X
Shan
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Hazel
H
Lum
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Xiaokun
X
Li
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Guang
G
Liang
D000804:Angiotensin II / Q000009:adverse effects / Q000378:metabolism*; D000818:Animals; D001706:Biopsy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases; D005355:Fibrosis; D018836:Inflammation Mediators / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases