Klotho protein inhibits H2O2-induced oxidative injury in endothelial cells via regulation of PI3K/AKT/Nrf2/HO-1 pathways

• Published in: Canadian journal of physiology and pharmacology Vol. 97; no. 5; pp. 370 - 376
• Main Authors: Cui, Wei, Leng, Bin, Wang, GaoPin
• Format: Journal Article
• Language: English
• Published: Canada NRC Research Press 01.05.2019; Canadian Science Publishing NRC Research Press
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; AKT protein; Antioxidants; Apoptosis; Cardiovascular system; Catalase; Cell viability; Cells; cellules endothéliales; Endothelial cells; Enzymes; Heme; Heme oxygenase (decyclizing); Hydrogen peroxide; Inflammation; Injuries; Interleukin 6; Kinases; Klotho; Klotho protein; LY294002; lésions oxydatives; Nitric oxide; Nuclear transport; Organs; oxidative injury; Oxidative stress; Oxygenase; Pharmacology; Phosphorylation; Physiology; PI3K/AKT/Nrf2/HO-1; Protein transport; Proteins; Reactive oxygen species; Secretion; Studies; Superoxide; Superoxide dismutase; Translocation; Tumor necrosis factor-α; Umbilical vein; Veins; Viability
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2018-0277

Klotho protein secreted in the blood could act as a hormone to regulate various target organs and have a protective effect on the cardiovascular system. Numerous studies had shown that Klotho protein had antioxidative stress, anti-inflammatory, and antiapoptotic effects on vascular endothelial cells. The purpose of this study was to investigate the protective mechanism of Klotho protein on oxidative damage of vascular endothelial cells induced by H 2 O 2 . Klotho protein significantly enhanced human umbilical vein endothelial cells viability and increased the activities of antioxidant enzymes (superoxide dismutase, catalase, and heme oxygenase-1 (HO-1)), scavenged reactive oxygen species, and inhibited tumor necrosis factor alpha and interleukin 6 secretion. Klotho protein also reduced the rate of apoptosis of cells and improved the function of vascular endothelial cells (increased nitric oxide secretion). Klotho protein activated nuclear translocation of Nrf2 and increased HO-1 expression. Klotho protein also activated phosphorylation of protein kinase B (AKT), whereas the addition of LY294002, a pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked Klotho-protein-induced Nrf2/HO-1 activation and cytoprotection. Klotho protein enhanced the antioxidant defense ability of the cells by activating the PI3K/AKT pathway, which upregulated the expression of Nrf2/HO-1, thereby inhibiting H 2 O 2 -induced oxidative damage.