Molecular basis for a link between complement and the vascular complications of diabetes

Abstract

Activated terminal complement proteins C5b to C9 form the membrane attack complex (MAC) pore. Insertion of the MAC into endothelial cell membranes causes the release of growth factors that stimulate tissue growth and proliferation. The complement regulatory membrane protein CD59 restricts MAC formation. Because increased cell proliferation characterizes the major chronic vascular complications of human diabetes and because increased glucose levels in diabetes cause protein glycation and impairment of protein function, we investigated whether glycation could inhibit CD59. Glycation-inactivation of CD59 would cause increased MAC deposition and MAC-stimulated cell proliferation. Here, we report that (i) human CD59 is glycated in vivo, (ii) glycated human CD59 loses its MAC-inhibitory function, and (iii) inactivation of CD59 increases MAC-induced growth factor release from endothelial cells. We demonstrate by site-directed mutagenesis that residues K41 and H44 form a preferential glycation motif in human CD59. The presence of this glycation motif in human CD59, but not in CD59 of other species, may help explain the distinct propensity of humans to develop vascular proliferative complications of diabetes.

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

“…CD59, prevent formation of MACs on the self-tissue. The increased blood glucose in diabetic patients could induce glycation of complement regulatory proteins and by this mean inactivate the proteins [38]. Glycation of CD59 happens in vivo in humans, but not in C57 mice.…”

“…Glycation of CD59 happens in vivo in humans, but not in C57 mice. This glycation attenuates its capacity to inhibit MAC formation [38]. It has been shown that MAC formation happens on cells and can lead to the release of growth factors without effects on cell viability [39].…”

Increased All-Cause Mortality in Patients With Type 1 Diabetes and High-Expression Mannan-Binding Lectin Genotypes: A 12-Year Follow-up Study

“…As shown in vitro, complement activation and sublytic formation of the terminal complement complex on mammalian cells may induce release of growth factors, leading to vascular alternations (26)(27)(28)(29)(30)(31). In addition, glycation of complement regulatory proteins has been shown to decrease their regulatory capacity and increase complement activation in diabetes (32,33). These mechanisms might contribute to development of late diabetes complications and to the excess mortality in diabetes.…”

Association between red blood cell distribution width and macrovascular and microvascular complications in diabetes

“…Likewise, increased concentrations of inflammatory markers, such as CRP and interleukin-6, have been involved in the development and progression of long-term diabetic macrovascular complications [18]. On the other hand, a shortened erythrocyte half-life has been reported in diabetes [19] and the metabolic syndrome has been related to increased RDW levels [20], leading us to postulate a possible influence of an underlying inflammatory state (the occurrence of which is typical in diabetes mellitus and the metabolic syndrome [18]) on accelerated erythrocyte destruction. In the present study, we observed increased CRP levels in the quartiles with highest RDW.…”