The Emerging Roles of Microparticles in Diabetic Nephropathy

Abstract

Microparticles (MPs) are a type of extracellular vesicles (EVs) shed from the outward budding of plasma membranes during cell apoptosis and/or activation. These microsized particles then release specific contents (e.g., lipids, proteins, microRNAs) which are active participants in a wide range of both physiological and pathological processes at the molecular level, e.g., coagulation and angiogenesis, inflammation, immune responses. Research limitations, such as confusing nomenclature and overlapping classification, have impeded our comprehension of these tiny molecules. Diabetic nephropathy (DN) is currently the greatest contributor to end-stage renal diseases (ESRD) worldwide, and its public health impact will continue to grow due to the persistent increase in the prevalence of diabetes mellitus (DM). MPs have recently been considered as potentially involved in DN onset and progression, and this review juxtaposes some of the research updates about the possible mechanisms from several relevant aspects and insights into the therapeutic perspectives of MPs in clinical management and pharmacological treatment of DN patients.

Keywords: diabetic nephropathy; endoplasmic reticulum stress; insulin resistence; microparticles; transcellular crosstalk; vascular endothelial growth factor A..

Figure 1

The formation of MPs. When stimulated by external factors (e.g., inflammation, apoptosis), intracellular calpain and phosphatase are, respectively, activated and inhibited, reorganizing the cytoskeleton via three enzymes (flippases, floppases and scramblase) and phosphatidylserine (PS) exposure from the inner monolayer to the MP surface, all of which led to the final vesiculation and outward budding of the plasma membrane.

Figure 2

MPs are involved in DN pathogenesis. With demonstrable increases in DN-related pathological contexts, MPs might be involved in DN via the mechanisms, including (1) Mediating transcellular crosstalk mainly by (a) delivering their content to recipient cells and releasing these bioactive substances or (b) binding to the target cell receptors via surface molecules (namely, receptor-ligand interaction); (2) Promoting partial or systemic IR, possibly by influencing the insulin-related Akt/PI3K signalling and blocking glucose uptake by hindering glucose transporter (GLUT); (3) Increasing the production of cytosolic ROS, which activates organelle oxidative stress of mitochondria and ER and triggers inflammatory responses; (4) Exerting functions associated with angiogenesis and apoptosis and communicating between podocytes and glomerular endothelial cells via the VEGF-A/VEGFR-2 system.