Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2)

Zheng Xu,Weixin Li,Guang Liang,Chunpeng Zou,Weijian Huang,Jibo Han,Hazel Lum,Weihui Yu,Xiaokun Li,Xiaoou Shan

doi:10.1038/srep44911

Abstract

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.

Highlights

Chronic kidney diseases (CKD), a growing world-wide health problem, can progress to the serious end-stage kidney disease, in which patients require dialysis or a kidney transplant[1,2]
We tested the hypothesis that angiotensin II (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
Our findings indicated that the subcutaneous injection of Ang II into mice resulted of renal dysfunction, as indicated by abnormal levels of serum creatinine, albuminuria (ALB)/creatinine ratio, and blood urea nitrogen (BUN) (Fig. 1A–C)

Summary

Introduction

Chronic kidney diseases (CKD), a growing world-wide health problem, can progress to the serious end-stage kidney disease, in which patients require dialysis or a kidney transplant[1,2]. Despite the growing evidence for TLR4’s role as a key factor in mediating the inflammatory injury and fibrosis of CKD, the specific mechanism of activation of this potential pathogenic pathway of CKD remains unclear. In a mouse model of CKD using Ang II infusion, mice with the mutant non-functional TLR4 are protected from developing albuminuria, elevated serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis[7]. These findings suggest a mechanism by which Ang II signals downstream pro-inflammatory targets in a TLR4-dependent manner. We conclude that MD2 is a significant contributor in the Ang II-induced kidney tissue injury and remodeling, and could be a new and important therapeutic strategy for preventing progression of chronic renal diseases

Methods

Results

Conclusion