The accumulation of advanced oxidation protein products (AOPPs) has been linked to vascular lesions in diabetes, chronic renal insufficiency, and atherosclerosis. However, the signaling pathway involved in AOPPs-induced endothelial cells (ECs) perturbation is unknown and was investigated. AOPPs modified human serum albumin (AOPPs-HSA) bound to the receptor for advanced glycation end products (RAGE) in a dose-dependent and saturable manner. AOPPs-HSA competitively inhibited the binding of soluble RAGE (sRAGE) with its preferential ligands advanced glycation end products (AGEs). Incubation of AOPPs, either prepared in vitro or isolated from uremic serum, with human umbilical vein ECs induced superoxide generation, activation of NAD(P)H oxidase, ERK 1/2 and p38, and nuclear translocation of NF-kappaB. Activation of signaling pathway by AOPPs-ECs interaction resulted in overexpression of VCAM-1 and ICAM-1 at both gene and protein levels. This AOPPs-triggered biochemical cascade in ECs was prevented by blocking RAGE with either anti-RAGE IgG or excess sRAGE, but was not affected by the neutralizing anti-AGEs IgG. These data suggested that AOPPs might be new ligands of endothelial RAGE. AOPPs-HSA activates vascular ECs via RAGE-mediated signals.

Accumulation of plasma advanced oxidation protein products (AOPP) has been found in patients with chronic kidney disease. However, the biologic consequences of AOPP consumption on progression of renal disease still are unclear. For testing of the hypothesis that AOPP accelerate progression of chronic kidney disease, Sprague-Dawley rats were subjected to five-sixths nephrectomy (5/6 Nx) or to sham operation. Rats in each group were randomly assigned in three subgroups (n ‫؍‬ 30 in each group) and treated with repeated intravenous injections of AOPP-modified rat serum albumin (RSA), unmodified RSA, or vehicle for indicated period. Compared with RSA-or vehicle-treated 5/6 Nx rats, AOPP RSA-treated 5/6 Nx rats displayed greater proteinuria, higher serum creatinine, and lower creatinine clearance. AOPP challenge resulted in more renal hypertrophy, higher macrophage influx, and greater renal fibrosis in the remnant kidney. Chronic administration of AOPP in sham-operated rats increased urinary protein excretion and renal macrophage infiltration, but histologic renal fibrosis was not observed during the study period. AOPP treatment enhanced AOPP level in renal tissue. This was associated with marked increase of thiobarbituric acid reactive substances, decrease of glutathione peroxidase activity, and upregulated expression of monocyte chemoattractant protein-1 and TGF-␤1 in renal cortex. These data indicate that AOPP might be a new and potentially important mediator of renal fibrosis in the remnant kidney. Chronic accumulation of AOPP promotes renal fibrosis probably via a redox-sensitive inflammatory pathway.

Patients with chronic renal failure are characterized by increased plasma levels of C‐reactive protein (CRP) and advanced glycation end products (AGE). AGE have been identified as a class of proinflammator mediators. To investigate whether AGE can stimulate hepatocytes to produce CRP, primary human fetal hepatocytes (HFH) were incubated with AGE‐modified human serum albumin (AGE‐HSA) or conditioned medium from AGE‐HSA‐stimulated monocytes (AGE‐MCM). CRP concentrations in the supernatants were determined by an ELISA and CRP mRNA levels were determined by a quantitative RT‐PCR. Exposure of HFH with AGE‐HSA for 12–72 h did not change CRP concentrations in the supernatants. CRP protein and mRNA expression were significantly upregulated in a time‐ and dose‐dependent manner when HFH were incubated with AGE‐MCM. This stimulating effect was partially inhibited when AGE‐MCM were preincubated with antibodies against interleukin‐6 (anti‐IL‐6), interleukin‐1β (anti‐IL‐1β), or soluble IL‐1 receptor and was completely inhibited when AGE‐MCM were preincubated with anti‐IL‐6 and anti‐IL‐1β simultaneously. The inhibiting effect did not occur when AGE‐MCM was preincubated with antibody of tumour necrosis factor‐α (anti‐TNF‐α) and soluble TNF receptor. Exposure of HFH with exogenous IL‐6 and IL‐1β, at the same concentrations as contained in AGE‐MCM, also increased CRP production, but exogenous TNF‐α had no effect. These results suggest that AGE cannot directly stimulate hepatocytes to produce CRP, but rather indirectly enhance CRP expression via stimulation of IL‐6 and IL‐1β production by human monocytes.

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