Thus, purified lycopene was bioavailable and was shown to decrease DNA oxidative damage and urinary 8-OHdG at the high dose.

Diabetic nephropathy is an increasingly important cause of morbidity and mortality worldwide. A large body of evidence suggests that dyslipidemia has an important role in the progression of kidney disease in patients with diabetes. Lipids may induce renal injury by stimulating TGF-beta, thereby inducing the production of reactive oxygen species and causing damage to the glomeruli and glomerular glycocalyx. Findings from basic and clinical studies strongly suggest that excess amounts of a variety of lipoproteins and lipids worsens diabetes-associated microvascular and macrovascular disease, increases glomerular injury, increases tubulointerstitial fibrosis, and accelerates the progression of diabetic nephropathy. The increasing prevalence of obesity, type 2 diabetes mellitus, and diabetic nephropathy means that interventions that can interrupt the pathophysiological cascade of events induced by lipoproteins and lipids could enable major life and cost savings. This Review discusses the structural, cellular, and microscopic findings associated with diabetic nephropathy and the influence of lipoproteins, specifically triglyceride-rich lipoproteins (TGRLs), on the development and perpetuation of diabetic nephropathy. Some of the accepted and hypothesized mechanisms of renal injury relating to TGRLs are also described.

Angiotensin II (angII) is known to promote atherosclerosis; however, the mechanisms involved are not fully understood. To determine whether angII stimulates proteoglycan production and LDL retention, LDL receptordeficient mice were infused with angII (1,000 ng/kg/min) or saline via osmotic minipumps. To control for the hypertensive effect of angII, a parallel group received norepinephrine (NE; 5.6 mg/kg/day). Arterial lipid accumulation was evaluated by measuring the retention rate of LDL in isolated carotid arteries perfused ex vivo. Mice infused with angII had increased vascular content of biglycan and perlecan and retained twice as much LDL as saline-or NEinfused mice, although no group developed atherosclerosis at this time. To determine whether this increase in biglycan and perlecan content predisposed to atherosclerosis development, mice were infused with angII, saline, or NE for 4 weeks, then pumps were removed and mice received an atherogenic Western diet for another 6 weeks. Mice that had received angII infusions had 3-fold increased atherosclerosis compared with mice that had received saline or NE, and apolipoprotein B colocalized with both proteoglycans. Thus, one mechanism by which angII promotes atherosclerosis is increased proteoglycan synthesis and increased arterial LDL retention, which precedes and contributes to atherosclerosis

Objective Elevation of triglyceride-rich lipoproteins (TGRL) contributes to the risk for atherosclerotic cardiovascular disease (ASCVD). Our work has shown that TGRL lipolysis products in high physiological to pathophysiological concentrations cause endothelial cell injury; however, the mechanisms remain to be delineated. Approach and Results We analyzed the transcriptional signaling networks in arterial endothelial cells exposed to TGRL lipolysis products. When human aortic endothelial cells (HAEC) in culture were exposed to TGRL lipolysis products, activating transcription factor 3 (ATF3) was identified as a principal response gene. Induction of ATF3 mRNA and protein was confirmed by qRT-PCR and western blot. Immunofluorescence analysis showed that ATF3 accumulated in the nuclei of cells treated with lipolysis products. Nuclear expression of p-JNK, previously shown to be an initiator of the ATF3 signaling cascade, also was demonstrated. siRNA-mediated inhibition of ATF3 blocked lipolysis products-induced transcription of E-selectin and IL-8, but not IL-6 or NFκB. c-Jun, a downstream protein in the JNK pathway was phosphorylated while expression of NFκB-dependant JunB was down-regulated. Additionally, JNK siRNA suppressed ATF3 and p-c-Jun protein expression suggesting that JNK is up-stream of the ATF3 signaling pathway. In vivo studies demonstrated that infusion of TGRL lipolysis products into wild type mice induced nuclear ATF3 accumulation in carotid artery endothelium. ATF3−/− mice were resistant to vascular apoptosis precipitated by treatment with TGRL lipolysis products. Also peripheral blood monocytes isolated from postprandial humans had increased ATF3 expression as compared to fasting monocytes. Conclusion This study demonstrates that TGRL lipolysis products activate ATF3-JNK transcription factor networks and induce endothelial cells inflammatory response.

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