High Mobility Group Box-1: A Missing Link between Diabetes and Its Complications
High Mobility Group Box-1: A Missing Link between Diabetes and Its Complications
Han Wu, Zheng Chen, Jun Xie, Li-Na Kang, Lian Wang, and Biao Xu
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China
Received 20 May 2016; Accepted 3 October 2016
Academic Editor: Mirella Giovarelli
Copyright © 2016 Han Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
High mobility group box-1 (HMGB-1), a damage-associated molecular pattern, can be actively or passively released from various cells under different conditions and plays a pivotal role in the pathogenesis of inflammation and angiogenesis-dependent diseases. More and more evidence suggests that inflammation, in addition to its role in progression of diabetes, also promotes initiation and development of diabetic complications. In this review, we focus on the role of HMGB-1 in diabetes-related complications and the therapeutic strategies targeting HMGB-1 in diabetic complications.
1. Introduction
Diabetes is evolving as an epidemic disease, which affects about 400 million people worldwide. It is a metabolic disorder characterized by hyperglycemia due to defective insulin secretion or insulin resistance. Growing evidence on the involvement of inflammation in diabetes has made it an attractive topic. HMGB-1, an inflammatory mediator, can be released from various cells under different stress conditions. Over the past decade, a great gain of information about HMGB-1 in inflammatory diseases has been made. This review will give an overview of recent advances in HMGB-1 in diabetes, diabetic cardiovascular complications, diabetic nephropathy (DN), and diabetic retinopathy (DR), and then we will focus on therapeutic strategies targeting HMGB-1.
2. Introduction of HMGB-1
We will first introduce some definitions that will be used throughout the manuscript. These include ROS (reactive oxygen species), RAGE (receptor for advanced glycation end product), TLR2 (Toll-like receptor-2), TLR4 (Toll-like receptor-4), NF-κB (nuclear factor-κB), MyD88 (myeloid differentiation factor-88), p38MAPK (p38 mitogen-activated protein kinase), ERK (extracellular signal-regulated kinase), and JNK (c-Jun N-terminal kinase).
HMGB-1, a member of HMG protein superfamily, was first named 40 years ago because of its high mobility in polyacrylamide gel electrophoresis system [1, 2]. Human HMGB-1 is an about 30 kDa protein consisting of 215 amino acids and includes three distinct domains: two positive charged domains (A-box and B-box) composed of about 80 amino acids separately and a negatively charged acidic C-terminal tail composed of 30 amino acids. Furthermore, another 24 amino acids are used to link the domains [3]. HMG boxes A and B are able to mediate DNA binding, while the acidic C-tail can regulate the affinity of binding to distorted DNA structures via binding to other nuclear proteins [4] (Figure 1).
Figure 1: Schema depicting the structure of HMGB-1 and the molecular mechanisms responsible for the role of HMGB-1 in inflammation. (a) HMGB-1 translocates from the nucleus to the cytoplasm under oxidative stress condition and then is actively (immune or active inflammatory cells) or passively (death, apoptosis, or necrosis cells) released outside the cells. Once it is released into the extracellular space, HMGB-1 in turn promotes oxidative stress by binding to its receptors (such as RAGE, TLR2, and TLR4). (b) Extracellular HMGB-1 binds to its receptors and induces inflammatory response via various signaling pathways involving NF-κB, MyD88, p38MAPK, ERK, and JNK.
HMGB-1 is a ubiquitous nuclear protein for maintaining DNA structure in various cells, but it can be actively or passively released under stress conditions. For example, in inflammation-associated immune cells such as monocytes and macrophages, HGMB-1 translocates from nuclear to special cytoplasmic organelles and is actively released outside the cells under stress. Besides, HMGB-1 may fail to bind to chromatin and is passively released into the extracellular space from cells undergoing necrosis, apoptosis, and injury [5]. However, secretion of HMGB-1 was recently shown to be negatively regulated by haptoglobin. Yang et al. found that haptoglobin-HMGB-1 complexes elicited anti-inflammatory cytokines in macrophages, suggesting a mechanism for haptoglobin modulation of HMGB-1 action [6] (Figure 1(a)).
Once it is released outside the cells, extracellular HMGB-1 functions as a multifunctional cytokine in many pathophysiological processes. There are several receptors for HGMB-1, but of importance are receptor for advanced glycation end product (RAGE), Toll-like receptor-2 (TLR2), and Toll-like receptor-4 (TLR4) [7]. By binding to its receptors, HMGB-1 induces nuclear translocation of activated nucle (...truncated)