Exosomes: Biomarkers and Therapeutic Targets of Diabetic Vascular Complications

Abstract

Diabetic vascular complications (DVC) including macrovascular and microvascular lesions, have a significant impact on public health, and lead to increased patient mortality. Disordered intercellular cascades play a vital role in diabetic systemic vasculopathy. Exosomes participate in the abnormal signal transduction of local vascular cells and mediate the transmission of metabolic disorder signal molecules in distant organs and cells through the blood circulation. They can store different signaling molecules in the membrane structure and release them into the blood, urine, and tears. In recent years, the carrier value and therapeutic effect of exosomes derived from stem cells have garnered attention. Exosomes are not only a promising biomarker but also a potential target and tool for the treatment of DVC. This review explored changes in the production process of exosomes in the diabetic microenvironment and exosomes' early warning role in DVC from different systems and their pathological processes. On the basis of these findings, we discussed the future direction of exosomes in the treatment of DVC, and the current limitations of exosomes in DVC research.

Keywords: atherosclerosis; diabetic kidney disease (DKD); diabetic retinopathy (DR); diabetic vascular complications (DVC); exosome; stem cells.

Figure 1

Schematic diagram of exosomes production and reception. Exosomes are originated from the MVBs, referring to double invagination of the plasma membrane. Early sorting endosomes (ESEs) are formed by plasma membrane invagination, which can be fused with the endoplasmic reticulum (ER) and trans-Golgi network (TGN) to produce late sorting endosomes (LSEs). The second invagination in LSE leads to the formation of intraluminal vesicles (ILV). MVBs are formed from LSEs with several ILVs under two mechanisms, ESCRT-dependent and ESCRT-independent pathway. Some MVBs can be degraded by fusion with autophagy or lysosome, while others can be transported to the plasma membrane and released to the extracellular environment. Exosomes are composed of various proteins, lipids, DNA, and RNA. The released exosomes are mainly uptaken by recipient cells through three pathways, including endocytosis, direct fusion, and receptor-ligand interaction.

Figure 2

Schematic representation of exosomes regulating the pathological process of diabetic vascular complications. Exosomes mediate atherosclerosis and plaque rupture by regulating the production of no in aortic endothelium, increasing adhesion molecules, inflammatory transformation of macrophages, and endothelial proliferation in diabetes. In the retina, exosomes promote angiogenesis, destroy endothelial cells and increase leakage. At the same time, exosomes mediate the apoptosis of Müller cells in the early stage of DR and the proliferation and fibrosis of Müller cells in the late stage of DR. Exosomes carrying proteins and microRNAs mediate podocyte injury, basement membrane thickening, mesangial dilatation, and glomerulosclerosis in diabetic patients. Exosomes derived from stem cells can accelerate wound healing by regulating the proliferation and migration of fibroblasts and vascular endothelial cells.