Hsing Ru Tien

National Chung Hsing University, 臺中市, Taiwan, Taiwan

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Publications (3)18.87 Total impact

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    ABSTRACT: Aims: Activation of glomerular mesangial cells (MCs) and functional changes of renal tubular cells are due to metabolic abnormalities, oxidative stress, and matrix accumulation in the diabetic nephropathy (DN). Aryl hydrocarbon receptor (AhR) activation has been implicated in DN. Here, we investigated the role of AhR in the pathophysiological processes of DN using AhR-knockout (AhRKO) and pharmacological inhibitor α-naphthoflavone mouse models. Results: The increased blood glucose, glucose intolerance, MCs activation, macrophage infiltration, and extracellular matrix (ECM) accumulation were significantly attenuated in AhRKO mice with diabetic inducer streptozotocin (STZ) treatment. AhR deficiency by genetic knockout or pharmacological inhibition also decreased the induction of cyclooxygenase (COX)-2/prostaglandin (PG) E2, lipid peroxidation, oxidative stress, NADPH oxidase activity, and Nε-carboxymethyllysine (CML, a major advanced glycation end-products) in STZ-induced diabetic mice. CML showed remarkably increased AhR/COX-2 DNA binding activity, protein-DNA interactions, gene regulation, and ECM formation in mesangial cells and renal proximal tubular cells, which could be reversed by siRNA-AhR transfection. CML-increased AhR nuclear translocation and biological activity in MCs and renal proximal tubular cells could also be effectively attenuated by antioxidants. Innovation: We elucidate for the first time that AhR plays an important role in MCs activation, macrophage infiltration and ECM accumulation in DN conferred by oxidative stress. Conclusions: AhR-regulated COX-2/PGE2 expression and ECM deposition through oxidative stress cascade is involved in the CML-triggered mesangial cells activation and macrophage infiltration. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic micro-vascular complications.
    No preview · Article · Sep 2015 · Antioxidants & Redox Signaling
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    ABSTRACT: In response to aggravation by activated microglia, IL-13 can significantly enhance endoplasmic reticulum stress induction, apoptosis, and death via reciprocal signaling through C/EBPα and C/EBPβ. This reciprocal signaling promotes neuronal survival. Since the induction of COX-2 and PPARγ/HO-1 by IL-13 plays a crucial role in the promotion of and protection from activated microglia respectively, here we investigated the role of IL-13 in regulating C/EBPs in activated microglia and determined its correlation with neuronal function. The results revealed that IL-13 significantly enhanced C/EBPα/COX-2 expression and PGE2 production in LPS-treated microglial cells. Paradoxically, IL-13 abolished C/EBPβ/PPARγ/HO-1 expression. IL-13 also enhanced ER stress-evoked calpain activation by promoting the association of C/EBPβ and PPARγ. SiRNA-C/EBPα effectively reversed the combined LPS-activated caspase-12 activation and IL-13-induced apoptosis. In contrast, siRNA-C/EBPβ partially increased microglial cell apoptosis. By NeuN immunochemistry and CD11b staining, there was improvement in the loss of CA3 neuronal cells after intra-hippocampal injection of IL-13. This suggests that IL-13-enhanced PLA2 activity regulates COX-2/PGE2 expression through C/EBPα activation. In parallel, ER stress-related calpain downregulates the PPARγ/HO-1 pathway via C/EBPβ and leads to aggravated death of activated microglia via IL-13, thereby preventing cerebral inflammation and neuronal injury. This article is protected by copyright. All rights reserved.
    Full-text · Article · Nov 2013 · European Journal of Immunology
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    ABSTRACT: N(ε) -carboxymethyllysine (CML), a major advanced glycation end product, plays a crucial role in diabetes-induced vascular injury. The roles of protein tyrosine phosphatases and vascular endothelial growth factor (VEGF) receptors in CML-related endothelial cell injury are still unclear. Human umbilical vein endothelial cell (HUVEC) is a commonly used human EC type. Here, we tested the hypothesis that NADPH oxidase/reactive oxygen species (ROS)-mediated SH2 domain-containing tyrosine phosphatase-1 (SHP-1) activation by CML inhibits the VEGF receptor-2 (VEGFR-2, KDR/Flk-1) activation, resulting in HUVEC injury. CML significantly inhibited cell proliferation and induced apoptosis and reduced VEGFR-2 activation in parallel with the increased SHP-1 protein expression and activity in HUVECs. Adding recombinant VEGF increased forward biological effects, which were attenuated by CML. The effects of CML on HUVECs were abolished by SHP-1 siRNA transfection. Exposure of HUVECs to CML also remarkably escalated the integration of SHP-1 with VEGFR-2. Consistently, SHP-1 siRNA transfection and pharmacological inhibitors could block this interaction and elevating [(3) H]thymidine incorporation. CML also markedly activated the NADPH oxidase and ROS production. The CML-increased SHP-1 activity in HUVECs was effectively attenuated by antioxidants. Moreover, the immunohistochemical stainings of SHP-1 and CML were increased, but phospho-VEGFR-2 staining was decreased in aortic endothelium of streptozotocin-induced and high-fat diet-induced diabetic mice. We conclude that a pathway of tyrosine phosphatase SHP-1-regulated VEGFR-2 dephosphorylation through NADPH oxidase-derived ROS is involved in the CML-triggered endothelial cell dysfunction/injury. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic vascular complications. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Full-text · Article · Jun 2013 · The Journal of Pathology