2003 Fiscal Year Final Research Report Summary
REACTIVE OXYGEN SPECIES FROM MITOCHONDRIA INDUCE CYCLOOXYGENASE-2 GENE EXPRESSION IN HUMAN MESANGIAL CELLS : POTENTIAL ROLE IN DIABETIC NEPHROPATHY
| Project/Area Number |
14571100
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | KUMAMOTO UNIVERSITY |
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Principal Investigator |
NISHIKAWA Takeshi KUMAMOTO UNIVERSITY, FACULTY OF MEDICAL AND PHARMACEUTICAL SCIENCES, FACULTY MEMBER, 大学院・医学薬学研究部, 助手 (70336212)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAMURA Nobuhiro KUMAMOTO UNIVERSITY, UNIVERSITY HOSPITAL, ASSISTANT PROFESSOR, 医学部附属病院, 講師 (40274716)
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| Project Period (FY) |
2002 – 2003
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| Keywords | DIABETS NELLITUS / DIABETIC NEPHROPATHY / GLOMERULAR HYPERFILTRATION / MITOCHONDRIA / OXIDATIVE STRESS / REACTIVE OXYGENSPECIES / CYCLOOXYGENASE-2 / NUCLEAR FACTOR κB |
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| Research Abstract |
Hyperglycemia increases the production of reactive oxygen species (ROS) from the mitochondrial electron transport chain in bovine endothelial cells (Nishikawa et al. 2000 ; Nature 404:787-90). Because several studies have postulated a role for prostaglandins (PGs) in the glomerular hyperfiltration seen in early diabetes, we evaluated the effect of mitochondrial ROS on expression of the inducible isoform of cyclooxygenase (COX-2) in cultured human mesangial cells (HMC). We first confirmed that incubation of HMC with 30 mM glucose significantly increased C0X-2 mRNA, but not COX-1 mRNA, compared with 5.6 mM glucose. Similarly, incubation of HMC with 30 mM glucose significantly increased mitochondrial membrane potential, intracellular ROS production, COX-2 protein expression and PGE_2 synthesis, and these events were completely suppressed by TTFA or CCCP, inhibitors of mitochondrial metabolism, or by overexpression of uncoupling protein-1 or manganese superoxide dismutase. In vivo study, it was confirmed that expression of COX-2 mRNA and protein was increased in glomeruli of diabetic mice. In addition, hyperglycemia induced activation of the COX-2 gene promoter, which was completely abrogated by mutation of two NF-κB (nuclear factor κB) binding sites in the promoter region. Our results suggest that hyperglycemia increases mitochondrial ROS production, resulting in NF-κB activation, COX-2 mRNA induction, COX-2 protein production and PGE_2 synthesis. This chain of events might contribute to the pathogenesis of diabetic nephropathy.
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[Publications] NISHIKAWA T, SASAHARA T, KIRITOSHI S, SONODA K, SENOKUCHI T, MATSUO T, KUKIDOME D, WAKE N, MATSUMURA T, MIYAMURA N, SAKAKIDA M, KISHIKAWA H, ARAKI E: "EVALUATION OF URINARY 8-HYDROXYDEOXYGUANOSINE AS A NOVEL BIOMAKER OF MACROVASCULAR COMPLICATIONS IN TYPE 2 DIABETES."DIABETES CARE. 26. 1507-1512 (2003)
Description
「研究成果報告書概要(欧文)」より
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[Publications] SAKAI K, MATSUMOTO K, NISHIKAWA T, SUEFUJI M, NAKAMARU K, HIRASHIMA Y, KAWASHIMA J, SHIROTANI T, ICHINOSE K, BROWNLEE M, ARAKI E: "MITOCHONDRIAL REACTIVE OXYGEN SPECIES REDUCE INSULIN SECRETION BY PANCREATIC β-CELLS."BIOCHEM BIOPHYS RES COMMUN. 300. 216-222 (2003)
Description
「研究成果報告書概要(欧文)」より
