Glycation Inactivation of the Complement Regulatory Protein CD59

Abstract

Micro-and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes. Diabetes 53: [2653][2654][2655][2656][2657][2658][2659][2660][2661] 2004

Analysis of the promoters and 5′-UTR of mouse Cd59 genes, and of their functional activity in erythrocytes

“…15,16 For example, we have shown that inactivation of CD59 by non-enzymatic glycation of its K41 residue causes increased MAC deposition, and that glycated CD59 colocalizes with MAC in human diabetic kidneys and nerves, two critical target tissues of diabetic complications. 17 Functionally, we have shown that decreased activity of CD59 in diabetic erythrocytes is associated with increased sensitivity to MAC-mediated lysis, 17 a similar result to that reported by Davies et al 18 Given the intrinsic difficulties in comprehensively studying the role of human CD59 in the pathogenesis of human disease, there is a strong need for an appropriate mouse model. For this reason, we decided to generate mice with either a loss (targeted deletion) or gain (transgenic expression) of CD59 function.…”

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

“…In another study, deposition of glycated CD59 was observed in the kidneys and nerves of diabetic patients, but not in nondiabetic patients. In about 60% of the same samples MACs were found colocalised with glycated CD59 [41]. Erythrocytes from diabetic patients were more susceptible to MACmediated lysis compared with those from non-diabetic subjects due to inactivation of CD59 by glycation [41].…”

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.…”