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Glycation Inactivation of the Complement Glycation Inactivation of the Complement Regulatory Protein CD59 A Possible Role in the Pathogenesis of the Vascular Complications of Human Diabetes Xuebin Qin,1,2 Allison Goldfine,3 Nicole Krumrei,2 Luciano Grubissich,2 Juan Acosta,2,4 Michael Chorev,2 Arthur P. Hays,5 and Jose A. Halperin1,2 Micro- and macrovascular diseases are major causes of evidence clearly demonstrates that prolonged hyperglyce- morbidity and mortality in the diabetic population, but mia underlies chronic complications of diabetes (1,2). the cellular and molecular mechanisms that link hyper- Hyperglycemia drives protein glycation, the nonenzymatic glycemia to these complications remain incompletely reaction of glucose with free ␣- or ε-amino groups in understood. We proposed that in human diabetes, inhi- proteins that results first in the formation of a Schiff base bition by glycation of the complement regulatory pro- or aldimine and then of the more stable ketoamine via the tein CD59 increases deposition of the membrane attack Amadori rearrangement. The ketoamine moiety can also complex (MAC) of complement, contributing to the undergo further rearrangements, leading to the formation higher vascular risk. We report here 1) the generation and characterization of an anti–glycated human CD59 of advanced glycation end products (AGEs) (3). When (hCD59) specific antibody, 2) the detection with this glycation involves its active site, the glycated protein may antibody of glycated hCD59 colocalized with MAC in lose function, as reported for glycated hemoglobin or AGE kidneys and nerves from diabetic but not from nondia- basic fibroblast growth factor (4). betic subjects, and 3) a significantly reduced activity of Consistent with a role of protein glycation in the patho- hCD59 in erythrocytes from diabetic subjects, a finding genesis of diabetic complications is the strong correlation consistent with glycation inactivation of hCD59 in vivo. found among hyperglycemia, protein glycation, and AGE Because hCD59 acts as a specific inhibitor of MAC formation. In addition to protein glycation, several mech- formation, these findings provide a molecular explana- anisms have been proposed to contribute to hyperglyce- tion for the increased MAC deposition reportedly found mic-related pathology, as reviewed recently (5). However, in the target organs of diabetic complications. We con- clude that glycation inactivation of hCD59 that leads to the cellular and molecular mechanisms by which hyper- increased MAC deposition may contribute to the exten- glycemia causes vascular damage still remain incom- sive vascular pathology that complicates human diabe- pletely understood. It is interesting that it has been noted tes. Diabetes 53:2653–2661, 2004 that humans are particularly prone to develop extensive vascular disease as a consequence of diabetes (6,7). We proposed that a novel mechanism that provides for in- creased vascular risk in humans with diabetes could icro- and macrovascular complications cause involve inactivation by glycation of the complement regu- substantial morbidity and mortality for pa- latory protein human CD59 (hCD59) (8). tients with diabetes, who are at higher risk The complement system consists of a group of Ͼ12 for heart disease and stroke, blindness, kid- soluble proteins that interact with one another in three Mney failure, and extremity amputations. Treatment of distinct enzymatic activation cascades known as the clas- chronic diabetic complications consumes nearly 15% of sical, alternative, and lectin pathways. All activation path- health care dollars in the U.S. Extensive epidemiological ways converge to form the membrane attack complex (MAC). The MAC is a circular polymer of 12–18 monomers From the 1Hematology Division, Department of Medicine, Brigham and of the C9 complement protein with the capacity to insert Women’s Hospital, Boston, Massachusetts; the 2Laboratory for Translational into cell membranes and form a transmembrane pore of an Research, Harvard Medical School, Boston, Massachusetts; the 3Joslin Diabe- tes Center, Boston, Massachusetts; 4Beth Israel Deaconess Medical Center, effective internal radius of 5–7 nm (9). Influx of salt and Boston, Massachusetts; and 5Columbia University, New York, New York. water through the MAC pore induces colloidosmotic swell- Address correspondence and reprint requests to Dr. Jose A. Halperin, ing and lysis of MAC-targeted cells such as gram-negative Harvard Medical School, 1 Kendall Square, Building 600, 3rd Floor, Cam- bridge, MA 02139. E-mail: [email protected]. bacteria or heterologous erythrocytes. We have demon- Received for publication 20 February 2004 and accepted in revised form 6 strated that during the assembly of the MAC pore, there is July 2004. X.Q. and A.G. contributed equally to this work. a phase when the MAC pore is transient and reversible, AGE, advanced glycation end product; DAF, decay-accelerating factor; permitting opening and closing/resealing of the plasma hCD59, human CD59; MAC, membrane attack complex; PMP, platelet-derived membrane (10–12). These transient MAC pores can gen- microparticle; PNH, paroxysmal nocturnal hemoglobinuria; RBC, red blood cell. erate significant changes in the membrane permeability of © 2004 by the American Diabetes Association. autologous cells without compromising their viability and DIABETES, VOL. 53, OCTOBER 2004 2653 GLYCATION-INHIBITION OF hCD59 IN DIABETES TABLE 1 Clinical characteristics of 12 patients with diabetic nephropathy Plasma Patient Age creatinine Proteinuria no. Sex (years) (mg/dl) (mg/24 h) Pathology 1 F 66 2.5 11 Diffuse intracapillary glomerulosclerosis with interstitial fibrosis 2 F 59 2.0 13 Glomerulosclerosis with nodule formation 3 F 55 5 2.5 Advance diffuse and nodular glomerulosclerosis 4 M 77 2.9 423 Diffuse and nodular diabetic glomerulosclerosis 5 F 52 N/A N/A Diffuse and nodular diabetic glomerulosclerosis moderately advanced 6 F 45 N/A N/A Diffuse mesangial sclerosis 7 M 55 3.5 170 Diffuse intracapillary glomerulosclerosis with priminent hyaline arteriolar sclerosis 8 M 59 1.8 233 Diffuse and nodular diabetic glomerulosclerosis moderately advanced 9 F 50 N/A N/A Intracapillar glomerulosclerosis with interstitial fibrosis 10 M 71 2.7 Ͼ55 Advanced diffuse and nodular glomerulosclerosis 11 M 62 1.8 233 Diffuse intracapillar glomerulosclerosis 12 F 46 2.3 Ͼ300 Glomerulosclerosis with interstitial fibrosis 13 N/A N/A N/A N/A N/A thereby mediate physiological and/or pathological re- tion in diabetic tissues has not been investigated in hu- sponses (13). For example, complement activation and mans. Here, we report an immunocytochemistry study in nonlytic MAC formation on endothelium activates endo- human diabetic and nondiabetic kidney and nerve biopsy thelial cells (14) and induces the release into the extracel- samples showing the presence of glycated hCD59 colocal- lular medium of growth factors such as basic fibroblast ized with MAC in diabetic but not in nondiabetic tissues. growth factor and platelet-derived growth factor (15,16), We also show that erythrocytes of diabetic patients have a interleukin-1 (12), monocyte chemotactic protein-1 (17), significantly reduced activity of hCD59 and increased and von Willebrand factor (18). Acting auto- and paracrini- sensitivity to MAC-mediated lysis. Together, these findings cally on extracellular receptors, these molecules released indicate that glycation inactivation of hCD59 may explain through the MAC pore, respectively, promote 1) prolifer- increased MAC deposits in diabetic tissues and contribute ation of fibroblasts and endothelial and smooth muscle at the molecular level to the vascular proliferative pathol- cells (15); 2) inflammation attracting monocytes and mac- ogy that complicates human diabetes. rophages to the site of focal complement activation (19), and inducing the expression of proinflammatory adhesion molecules such as E-selectin, vascular cell adhesion mol- RESEARCH DESIGN AND METHODS ecule-1, intracellular adhesion molecule-1 (20), and P- Human samples. Renal samples were obtained from the Pathology Depart- ment of Brigham and Women’s Hospital. Table 1 summarizes the renal selectin (14); and 3) thrombosis by inducing the function and pathological records of 12 of the 13 patients with diabetic expression of tissue factor (17) and the exposure of nephropathy. Nerve biopsies, provided by Dr. A. Hayes (Columbia-Presbyte- binding sites for clotting factor Va (21). rian, New York, NY), were the same samples reported previously (23). All To downregulate complement activity and protect “self” samples were obtained with approval by the institutional review boards of the respective institutions. cells from the catastrophic effect of complement activa- Generation of anti–glycated hCD59 polyclonal antibody. The antigen tion/amplification, Ͼ10 plasma- and membrane-bound in- was a 14–amino acid peptide (hCD5937–50) synthesized by solid-phase chem- hibitory proteins, including CD59, have evolved to restrict istry using an ε-glucitol-lysine residue at the position corresponding to lysine complement activation at different stages of the activation 41 in the native protein. This glycated peptide was conjugated to keyhole pathways. CD59, a key inhibitor of MAC formation, is a limpet hemocyanin and injected into rabbits for immunization as described previously (25). The antibody was purified from rabbit immune serum by glycan phosphatidylinositol-linked membrane protein that affinity chromatography with the antigen peptide. is universally expressed in cells. We have previously Production
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