Glycation Inactivation of the Complement Regulatory Protein CD59: A Possible Role in the Pathogenesis of the Vascular Complications of Human Diabetes (original) (raw)

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

Proceedings of The National Academy of Sciences, 2000

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

“Possible role of glycated complement proteins in progression of diabetic nephropathy”

Diabetic nephropathy has emerged as the single largest cause of chronic renal failure and leads to medical burden of end stage renal disease. The present study was conducted to evaluate serum protein glycation and its effect on complement fixation activity and antigen antibody reaction in Type 2 and Type 1 diabetic patients without or with nephropathy along with healthy control individuals. A positive correlation between fructosamine and lipid bound sialic acid was observed in Type 2 and Type 1 diabetic patients without nephropathy (R 2 =0.509, 0.621) and with Type 2 and Type 1 diabetic nephropathy patients (R 2 = 0.504, 0.0.663). A significant increase in the glycation of serum proteins was observed in all the studied groups as compared to the control. Type 1 diabetic patients without and with nephropathy showed 20 to 40 % higher levels of glycated proteins as compared to the patients with Type 2 diabetes mellitus of respective groups. The complement fixation activity of diabetic serum was higher than normal healthy individuals, where the patients with Type 2 and Type 1 diabetic nephropathy showed 128 % and 135 % higher binding respectively than with their respective group of patients with diabetes alone. The immuno-reactivity of IgG with anti-IgG was reduced in diabetic patients than normal healthy individuals, which was further decreased by 58 % and 80 % in Type 2 diabetic and Type 1 diabetic patients with nephropathy than with their respective group of patients with diabetes alone. This study reveals that excessive glycation of complement proteins may increase the complement binding efficiency in diabetes, which may have a role in the development of diabetic nephropathy and the instability of immune complexes may lead to decreased immunity of Type 1 and Type 2 diabetic patients.

Regulation of CD59 expression on the human endothelial cell line EA.hy 926

European Journal of Immunology, 1993

CD59 (protectin) is an 18-20-kDa inhibitor of the membrane attack complex of complement. It protects homologous cells from complement-mediated damage and has been shown to be present on the endothelial cell membranes both in vitro and in viva In this study we observed that the surface expression of CD59 on the cultured EA.hy 926 endothelial cell line can be up-regulated to an approximately threefold higher level after a 72-h stimulation by the protein kinase C inducers phorbol-12-myristate-13 acetate (PMA; 10 nM) and calcium ionophore, A23187 (100 nM). Similarly, an increase in the level of CD59 expression was seen by the protein kinase A inducer dibutyryl-cyclic adenosine monophosphate. In Northern blot analysis increases were observed in CD59 mRNA expression, particularly in the level of the longest 1.9-kb, 2.1-kb and 5.8-kb transcripts. A functional significance for the increased CD59 expression was implied by an observed increased resistance of the PMA-stimulated EA.hy 926 cells to complement-mediated cell lysis.

Increased Complement Activation in Human Type 1 Diabetes Pancreata

Diabetes Care, 2013

OBJECTIVEdEvidence supporting an association between complement (C) and type 1 diabetes (T1D) includes the identification of C-fixing islet cell autoantibodies in T1D sera and genetic associations with the major histocompatibility complex III C4 region on chromosome 6. Therefore, we investigated whether C activation was present in pancreata from those with or at increased risk (positive for T1D associated autoantibodies) for T1D.

The Role of Complement Cascade in Diabetic Kidney Disease: New Paradigms and Therapeutic Targets

International Journal of Innovative Research in Medical Science

Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus. DKD is a frequent entity, which occurs in approximately 30-40% of diabetic patients. Traditionally, DKD has been considered a non-inflammatory glomerular disease, being perceived as a condition induced primarily by metabolic and hemodynamic changes. Inflammation has been classified as a main phenomenon for the onset and progression of DKD. Today, the inclusion of the inflammatory component is fundamental for the comprehension of the onset and development of this disease. The inflammatory component has multiple pathways, within which the activation and regulation of the complement system is of particular interest. The mechanisms by which complement is part of the multiple inflammatory pathways in DKD are being increasingly understood, which will guide the development of strategies and therapeutic targets.

Effects of Complement Regulators and Chemokine Receptors in Type 2 Diabetes

Immunological Investigations, 2020

CD55 and CD59 are complement regulatory proteins suggested to be related with progression of diabetes and its complications. The stromal cell-derived factor 1 (SDF-1) and C-X-C chemokine receptor type 4 (CXCR-4) are chemokine proteins. We aimed to investigate the relation of CD55 and CD59 expression levels and polymorphisms of SDF-1 and CXCR-4 with type 2 diabetes mellitus (T2DM) and its complications. Seventy-five T2DM patients and 73 controls were enrolled. Expression levels of CD55 and CD59 were measured by FACS Calibur; qRT-PCR was used to determine SDF-1 and CXCR-4 gene polymorphisms. CD55 and CD59 expressions in patients with nephropathy, retinopathy and cardiovascular disease were significantly lower than controls. Frequency of CXCR-4 T allele carrying was high in patients and created 1.6 fold risk for the disease (p = .07). CXCR-4 a allele carriers had decreased nephropathy; although there was no statistical significance in carrying CXCR-4 T allele, presence of nephropathy was approximately 2 times higher (p = .254). The nephropathy risk increased 10-fold in CXCR-4 TT genotype carriers (p = .02). All SDF-1 CC genotype carriers had retinopathy, so, it was considered that the CC genotype was effective in retinopathy development (p = .031). For the presence of cardiovascular disease, significant difference was observed for SDF-1 genotypes. Increased cardiovascular risk of 5-and 1.9-fold in SDF-1 T (p = .007) and CXCR-4 T (p = .216) allele carriers, respectively, was observed. We suggest that CD55 and CD59 protein levels and SDF-1 and CXCR-4 have predictive importance in process, complications and tendency of T2DM.