Pterostilbene protects against uraemia serum-induced endothelial cell damage via activation of Keap1/Nrf2/HO-1 signaling.

Abstract

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.

• Authors: Zhi-Wei Chen, Hai-Feng Miu, Hui-Ping Wang, Zhi-Niu Wu, Wen-Juan Wang, Yu-Jing Ling, Xiao-Hui Xu, Hai-Jian Sun, Xia Jiang
• Journal: International urology and nephrology (Int Urol Nephrol) Vol. 50 Issue 3 Pg. 559-570 (Mar 2018) ISSN: 1573-2584 [Electronic] Netherlands
• PMID: 29094331 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Cytokines
• Enzyme Inhibitors
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• Metalloporphyrins
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Protoporphyrins
• RNA, Small Interfering
• Stilbenes
• pterostilbene
• tin protoporphyrin IX
• L-Lactate Dehydrogenase
• Catalase
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• HMOX1 protein, human
• Heme Oxygenase-1
• Superoxide Dismutase

Topics

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