Extracellular HMGB1 Induced Glomerular Endothelial Cell Injury via TLR4/MyD88 Signaling Pathway in Lupus Nephritis.

Tian Yu,Liu Qingjuan,Tian Yuexin,Zhao Hang,Feng Xiaojuan,Huang Jie,Xu Jie,Liu Jinxi,Gu Cunyang,Liu Shuxia,Wu Lunbi,Miao Xinyan,Guo Huifang,Zhang Wei,Qingdong Guan

doi:10.1155/2021/9993971

Abstract

Previously, our study showed that HMGB1 was significantly elevated in the blood and located in the glomerular endothelium in LN patients. But whether extracellular HMGB1 is involved in the injury of glomerular endothelial cells (GECs) in LN still needs further investigation. Firstly, we detected the levels of SDC-1, VCAM-1, and proteinuria in LN patients and MRL/lpr mice and analyzed their correlations. Then, HMGB1 and TLR4/MyD88 were inhibited to observe the shedding of glycocalyx and injury of GECs in vivo and in vitro. Our results showed that HRGEC injury and SDC-1 shedding played an important role in the increase of permeability and proteinuria formation in LN. Additionally, inhibition of extracellular HMGB1 and/or downstream TLR4/MyD88/NF-κB/p65 signaling pathway also alleviated GEC monolayer permeability, reduced the shedding of the glomerular endothelial glycocalyx, improved the intercellular tight junction and cytoskeletal arrangement, and downregulated the NO level and VCAM-1 expression. These results suggested that extracellular HMGB1 might involve in GEC injury by activating the TLR4/MyD88 signaling pathway in LN, which provided novel insights and potential therapeutic target for the treatment of lupus nephritis.

Highlights

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often involves multiple tissues and organs
Our results showed that inhibiting the High mobility group box 1 (HMGB1) and TLR4/MyD88 signaling pathway alleviated glycocalyx shedding and glomerular endothelial cells (GECs) injury in MRL/lpr mice and Lupus nephritis (LN) plasma-stimulated human renal GECs (HRGECs), which will provide a new direction for therapeutic target of endothelial injury and proteinuria in LN
The serum levels of SDC-1 and VCAM-1 in LN patients and controls were detected by enzyme-linked immunosorbent assay (ELISA)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often involves multiple tissues and organs. Lupus nephritis (LN) is one of the most serious complications of SLE and a major risk factor for morbidity and mortality [1]. Proteinuria is one of the most representative manifestations of LN, and the key pathological feature is the damage of the glomerular filtration barrier (GFB). Glomerular endothelium is the first layer of GFB, including glomerular endothelial cells (GECs), the glycocalyx covering the surface of the GECs, transcellular fenestrations, and tight junctions among cells [5]. Glomerular endothelial dysfunction contributes to hypertension, edema, and proteinuria [6]. The precise mechanism of GEC dysfunction in the pathogenesis of LN needs further research

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