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.

The Renoprotection of Optimal Antiproteinuric Doses (ROAD) study was performed to determine whether titration of benazepril or losartan to optimal antiproteinuric doses would safely improve the renal outcome in chronic renal insufficiency. . Uptitration was performed to optimal antiproteinuric and tolerated dosages, and then these dosages were maintained. Median follow-up was 3.7 yr. The primary end point was time to the composite of a doubling of the serum creatinine, ESRD, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease. Compared with the conventional dosages, optimal antiproteinuric dosages of benazepril and losartan that were achieved through uptitration were associated with a 51 and 53% reduction in the risk for the primary end point (P ‫؍‬ 0.028 and 0.022, respectively). Optimal antiproteinuric dosages of benazepril and losartan, at comparable BP control, achieved a greater reduction in both proteinuria and the rate of decline in renal function compared with their conventional dosages. There was no significant difference for the overall incidence of major adverse events between groups that were given conventional and optimal dosages in both arms. It is concluded that uptitration of benazepril or losartan against proteinuria conferred further benefit on renal outcome in patients who did not have diabetes and had proteinuria and renal insufficiency.

Objective-Increased level of plasma advanced oxidation protein products (AOPPs) has been found in patients with uremia and nonuremic subjects with coronary artery disease. This study was conducted to test the hypothesis that AOPPs play a causal role in atherosclerosis. Methods and Results-Hypercholesterolemic (0.5% wt/wt diet) or normal rabbits received either repeated intravenous injections of AOPPs modified rabbit serum albumin (AOPPs-RSA) or unmodified RSA for 8 weeks. Compared with RSA-or vehicle-treated hypercholesterolemic rabbits, AOPPs-RSA-treated animals displayed increased atherosclerotic plaque area oxidized low-density lipoprotein (oxLDL) deposition, macrophage infiltration, and smooth muscle cell proliferation. Aortic sections from AOPPs-RSA-treated normal rabbits showed significant focal intima proliferation and mild Oil-Red-O staining lipid deposition in the affected areas, a phenomenon not observed in the RSA-or vehicle-treated controls. Plasma AOPPs levels in AOPPs-treated groups significantly increased in both hypercholesterolemic and normal rabbits compared with their relevant controls. Close correlations were found between plasma levels of AOPPs and the parameters of oxidative stress, eg, oxLDL and thiobarbituric acid reactive substances levels, or glutathione peroxidase activity. A highly significant correlation was also observed between plasma AOPPs and tumor necrosis factor (TNF)-␣ levels. Key Words: advanced oxidation protein products Ⅲ atherosclerosis Ⅲ hypercholesterolemia Ⅲ inflammation Ⅲ oxidative stress T he high prevalence of atherosclerotic lesions has been amply documented in patients with chronic renal failure (CRF). 1,2 However, the factors that may promote atherosclerosis in CRF patients remain to be determined. Of particular importance in this context may be the recent observation of 3 who found that advanced oxidation protein products (AOPPs) significantly increased in patients with CRF. Conclusions-ThisBiochemical characterization has revealed that AOPPs are carried by plasma proteins, especially albumin. 3 AOPPs can be formed in vitro by exposure of serum albumin to hypochlorous acid (HOCl). In vivo, plasma concentration of AOPPs closely correlated with levels of dityrosine, a hallmark of oxidized protein, and pentosidine, a marker of protein glycoxidation tightly related to oxidative stress. 4 Thus, AOPPs might be formed during oxidative stress by reaction of plasma proteins with chlorinated oxidants, and have been considered as novel markers of oxidant-mediated protein damage. 3 More interesting is the finding that AOPPs are highly correlated to carotid intima media thickness 5 and may even be related to atherosclerotic cardiovascular events. 6 More recently, increased levels of AOPPs were also found in diabetic 7,8 and nonuremic subjects with coronary artery disease, 9 suggesting that accumulation of AOPPs may be relevant in atherosclerosis and not uremia-specific. However, although the observational studies suggest a close relationship between AOPPs and atherosclerosis,...

1,25-Dihydroxyvitamin D improved the FFA-induced insulin resistance in muscle cells.