title: Sinomenine alleviates high glucose-induced renal glomerular endothelial hyperpermeability by inhibiting the activation of RhoA/ROCK signaling pathway.
abstract: As an early sign of diabetic cardiovascular disease, endothelial dysfunction may contribute to progressive diabetic nephropathy (DN). Endothelial hyperpermeability induced by hyperglycemia (HG) is a central pathogenesis for DN. Sinomenine (SIN) has strong anti-inflammatory and renal protective effects, following an unknown protective mechanism against HG-induced hyperpermeability. We herein explored the role of SIN in vitro in an HG-induced barrier dysfunction model in human renal glomerular endothelial cells (HRGECs). The cells were exposed to SIN and/or HG for 24 h, the permeability of which was significantly increased by HG. Moreover, junction protein occludin in the cell-cell junction area and its total expression in HRGECs were significantly decreased by HG. However, the dysfunction of tight junction and hyperpermeability of HRGECs were significantly reversed by SIN. Furthermore, SIN prevented HG-increased reactive oxygen species (ROS) by activating nuclear factor-E2-related factor 2 (Nrf2). Interestingly, activation of RhoA/ROCK induced by HG was reversed by SIN or ROCK inhibitor. HG-induced hyperpermeability was prevented by SIN. High ROS level, tight junction dysfunction and RhoA/ROCK activation were significantly attenuated with knockdown of Nrf2. Mediated by activation of Nrf2, SIN managed to significantly prevent HG-disrupted renal endothelial barrier function by suppressing the RhoA/ROCK signaling pathway through reducing ROS. We successfully identified a novel pathway via which SIN exerted antioxidative and renal protective functions, and provided a molecular basis for potential SIN applications in treating DN vascular disorders.
authors.affiliation: Renal Department of Internal Medicine, The Third Hospital of Wuhan, PR China.
authors.forename: Qingqiao
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Renal Department of Internal Medicine, The Third Hospital of Wuhan, PR China. Electronic address: xiayuanyu.wh@gmail.com.
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, PR China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
mesh_terms: D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells; D005947:Glucose / Q000008:administration & dosage*; D006801:Humans; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D009019:Morphinans / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D009019:Morphinans; D017382:Reactive Oxygen Species; C066737:RHOA protein, human; C009271:sinomenine; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D005947:Glucose
keywords: High glucose; Hyperpermeability; Nrf2/ROS; Renal glomerular endothelial; RhoA/ROCK; Sinomenine