Identification of C1q as a Binding Protein for Advanced Glycation End Products

Abstract

Advanced glycation end products (AGEs) make up a heterogeneous group of molecules formed from the nonenzymatic reaction of reducing sugars with the free amino groups of proteins. The abundance of AGEs in a variety of age-related diseases, including diabetic complications and atherosclerosis, and their pathophysiological effects suggest the existence of innate defense mechanisms. Here we examined the presence of serum proteins that are capable of binding glycated bovine serum albumin (AGEs-BSA), prepared upon incubation of BSA with dehydroascorbate, and identified complement component C1q subcomponent subunit A as a novel AGE-binding protein in human serum. A molecular interaction analysis showed the specific binding of C1q to the AGEs-BSA. In addition, we identified DNA-binding regions of C1q, including a collagen-like domain, as the AGE-binding site and established that the amount of positive charge on the binding site was the determining factor. C1q indeed recognized several other modified proteins, including acylated proteins, suggesting that the binding specificity of C1q might be ascribed, at least in part, to the electronegative potential of the ligand proteins. We also observed that C1q was involved in the AGEs-BSA-activated deposition of complement proteins, C3b and C4b. In addition, the AGEs-BSA mediated the proteolytic cleavage of complement protein 5 to release C5a. These findings provide the first evidence of AGEs as a new ligand recognized by C1q, stimulating the C1q-dependent classical complement pathway.

Complement Activation in Peritoneal Dialysis–Induced Arteriolopathy

“…TCC inhibitor CD59 is suppressed by glycation and AGEs bind C1q and activate TCC downstream cascades, which induce the release of proinflammatory and prothrombotic cytokines and growth factors, promoting diabetic vasculopathy. [35][36][37] These findings are in line with our observations of peritoneal and omental endothelial complement activation correlating with intraperitoneal glucose exposure and with the degree of vasculopathy. PD fluids contain 10-40-fold supra-physiologic glucose concentrations, create a local diabetic milieu, and promote local and systemic AGE formation.…”

A novel association of CCDC80 with gestational diabetes mellitus in pregnant women: a propensity score analysis from a case-control study

“…Furthermore, component C1q, a marker of innate immune system, was also positively linked to circulating CCDC80 level. Previous studies have illustrated an advantageous effect of component C1q, which triggers activation of the classical pathway, in diabetes mellitus [29,30]. Finally, we detected that plasma CCDC80 level was positively associated with the dyslipidemia and atherosclerosis marker LDL-C, apoA1 and apoB.…”

Complement activation in patients with diabetic nephropathy

“…18 1810 (24) 27 14 (14) 0 (0) 1 (2) 5 53 712 2130 302 511 (19) 26 (26) Global 18 (44) 9 (16) 27 (27)…”