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

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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.

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Fig. 1: Effects of PT on HUVEC proliferation induced by US
Fig. 2: Effects of PT on oxidative stress in HUVECs induced by US
Fig. 3: Effects of PT on nitrative stress in HUVECs induced by US
Fig. 4: Effects of PT on inflammation response in HUVECs induced by US
Fig. 5: Effects of PT on Keap1/Nrf2/HO-1 signaling in HUVECs induced by US
Fig. 6: Effects of Nrf2-siRNA on PT-induced HO-1 expression in HUVECs
Fig. 7: Blockade of HO-1 with Snpp abolished the protective effects of PT on cell viability, oxidative stress and inflammatory response in HUVECs
Fig. 8: Blockade of HO-1 with Snpp abolished the protective effects of PT on nitrative stress in HUVECs
Fig. 9

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Acknowledgements

This work was supported by Fundamental Research Funds for the Central Universities (Grants No. JUSRP11745) and Project funded by China Postdoctoral Science Foundation (Grants No. 2017M611688). We gratefully thank Dr. H.J. Sun for his useful suggestion and help.

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  1. Zhi-Wei Chen, Hai-Feng Miu, Hui-** Wang and Zhi-Niu Wu have contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Center of Blood Purification, The Second People’s Hospital of Nantong, 43 **nglong Road, TangZha, Nantong, 226002, Jiangsu, People’s Republic of China

    Zhi-Wei Chen, Hai-Feng Miu, Wen-Juan Wang & **a Jiang

  2. Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu, People’s Republic of China

    Hui-** Wang, Zhi-Niu Wu, Yu-**g Ling, **ao-Hui Xu & Hai-Jian Sun

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  1. Zhi-Wei Chen
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Chen, ZW., Miu, HF., Wang, HP. et al. Pterostilbene protects against uraemia serum-induced endothelial cell damage via activation of Keap1/Nrf2/HO-1 signaling. Int Urol Nephrol 50, 559–570 (2018). https://doi.org/10.1007/s11255-017-1734-4

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