Abstract
Several studies have suggested that there is a link between membrane attack complex (MAC) deposition in the retina and the progression of diabetic retinopathy (DR). Our recent investigation demonstrated that circulating IgG-laden extracellular vesicles contribute to an increase in retinal vascular permeability in DR through activation of the complement system. However, the mechanism through which extracellular vesicle-induced complement activation contributes to retinal vascular cytolytic damage in DR is not well understood. In this study, we demonstrate that IgG-laden extracellular vesicles in rat plasma activate the classical complement pathway, and in vitro Streptozotocin (STZ)-induced rat diabetic plasma results in MAC deposition and cytolytic damage in human retinal endothelial cells (HRECs). Moreover, removal of the plasma extracellular vesicles reduced the MAC deposition and abrogated cytolytic damage seen in HRECs. Together, the results of this study demonstrate that complement activation by IgG-laden extracellular vesicles in plasma could lead to MAC deposition and contribute to endothelium damage and progression of DR.
Highlights
Extensive experimental and clinical evidence supports the link between complement system activation and the pathogenesis of diabetic vascular complications, including diabetic retinopathy (DR) and atherosclerosis [1,2]
An increased level of membrane attack complex (MAC) deposition found in the eyes of patients with DR when compared to eyes from non-diabetic subjects [5], is suggested to be the result of both the reduced levels of complement regulatory proteins and continued activation of the alternative pathway [6]
We investigated the physiological mechanism in which diabetic plasma extracellular vesicles induce complement activation leading to MAC deposition and cellular impairment in human retinal endothelial cells (HRECs)
Summary
Extensive experimental and clinical evidence supports the link between complement system activation and the pathogenesis of diabetic vascular complications, including diabetic retinopathy (DR) and atherosclerosis [1,2]. To prevent unintended damage to the host tissue by activated complement cascade, several complement regulatory proteins (CD55, CD46, and CD59) are anchored on the plasma membrane via a glyphosphatidylinositol. Aberrant complement activation and impairment of complement regulatory proteins in pathological conditions can lead to MAC formation on host cells [3,4]. We have reported that plasma extracellular vesicles activate the classical complement pathway, and may contribute to MAC-induced retinal vascular permeability in diabetes [14]. We investigated the physiological mechanism in which diabetic plasma extracellular vesicles induce complement activation leading to MAC deposition and cellular impairment in human retinal endothelial cells (HRECs)
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