stilbenes and Uremia

Chronic kidney disease causes uremia-related endothelial cell dysfunction associated with high risk for cardiovascular diseases. The vascular endothelium is permanently exposed to uraemic toxins including indoxyl sulfate, which provokes endothelial damage in subjects with end-stage renal disease. Pterostilbene (PT) is identified to be homologous derivative of resveratrol and exerts antioxidant and anti-inflammatory actions. However, the effects of PT on uraemic serum-induced endothelial cell damage have not been elucidated. In this study, we investigated the effects and mechanisms of PT on uraemic serum (US)-mediated injury in human umbilical vein endothelial cells (HUVECs). Treatment of US obviously reduced cell viability, inhibited superoxide dismutase activity and catalase activity, suppressed phosphorylated endothelial nitric oxide synthase (eNOS) protein level and eNOS activity, whereas promoted lactate dehydrogenase leakage, increased malondialdehyde, hydrogen peroxide, superoxide anions levels and NAD(P)H activity accompanied with increased nitrative stress and inflammatory response in HUVECs, and these changes were reversed after PT treatment. Under US environment, PT downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) protein levels. Of note, the level of HO-1 was decreased after the transfection of cells with Nrf2-siRNA, and HO-1 inhibitor Snpp abolished the protective effects of PT on HUVECs in response to US. Collectively, our study demonstrated that PT is effective in reducing US-evoked endothelial cell dysfunction via suppression of oxidative/nitrative stress and inflammatory response, which at least partly depended on Keap1/Nrf2/HO-1 signaling pathway.

Topics: Adult; Aged; Antioxidants; Catalase; Cell Proliferation; Cell Survival; Cells, Cultured; Cytokines; Enzyme Inhibitors; Female; Gene Expression; Heme Oxygenase-1; Human Umbilical Vein Endothelial Cells; Humans; Kelch-Like ECH-Associated Protein 1; L-Lactate Dehydrogenase; Male; Metalloporphyrins; Middle Aged; NF-E2-Related Factor 2; Nitric Oxide Synthase Type III; Oxidative Stress; Protoporphyrins; Renal Insufficiency, Chronic; RNA, Small Interfering; Serum; Signal Transduction; Stilbenes; Superoxide Dismutase; Uremia

The polyphenolic compound resveratrol (RSV) has been studied for its protective effects on a variety of conditions, including cardiovascular disease (CVD), reduced exercise capacity, and bone disease. Individuals with chronic kidney disease suffer from a variety of these comorbid conditions, but the efficacy of RSV supplementation in this population is unknown. The objective of this study was to determine the efficacy of resveratrol feeding on factors related to CVD, aerobic capacity, and bone health in a mouse model of uremia. At 8 weeks of age, 28 female apolipoprotein E⁻/⁻ mice underwent a two-step surgical procedure to induce uremia and were randomized to one of the two treatment groups for 16 weeks: 0.04% w/w resveratrol supplemented diet (group designated as RSV) (n=12) or control diet (group designated as CON) (n=16). Cardiovascular risk was determined by analysis of aortic atherosclerotic lesion area and aortic calcium, aerobic capacity was measured by maximal oxygen consumption/maximal aerobic capacity (VO(₂max)) testing, and bone microarchitecture was assessed by microcomputed tomography. RSV animals had significantly fewer aortic atherosclerotic lesions at the site of the ascending aorta and lower aortic calcium at the branch of the coronary arteries compared with CON. Furthermore, there was a significant decline in VO(₂max) from baseline to final testing in the CON group, but VO(₂max) was preserved in the RSV group. Last, RSV had no significant effect on bone architecture. These data indicate that RSV supplementation improves vascular health and preserves aerobic capacity in a model of uremia, suggesting RSV supplementation could be examined as a therapeutic strategy for a critically ill population.

Topics: Animals; Aorta; Calcinosis; Coronary Artery Disease; Dietary Supplements; Disease Models, Animal; Female; Humans; Mice; Oxygen; Resveratrol; Stilbenes; Uremia