| Project/Area Number |
14570078
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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 |
General pharmacology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
YOSHIZUMI Masanori The University of Tokushima, Department of Pharmacology, Lecturer, 医学部, 講師 (60294667)
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| Co-Investigator(Kenkyū-buntansha) |
KAGAMI Shoji Tokushima University Hospital, Pediatrics, Lecturer, 医学部・歯学部附属病院, 講師 (00224337)
TSUCHIYA Koichiro The University of Tokushima, Department of Clinical Pharmacology, Associate Professor, 歯学部, 助教授 (70301314)
TAMAKI Toshiaki The University of Tokushima, Department of Pharmacology, Professor, 医学部, 教授 (80179879)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | MAP kinase / Big MAP kinase 1 / diabetic nephropathy / mesangial cell / OLETF rat / Dahl rat / angiotensin II / antioxidant / Dahlラット / big MAP kinase 1 / oxidative stress / osmotic stress / diabetic nephrophthy / c-Src tyrosine kinase / protein kinase C / OLETF / mesangial cell |
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| Research Abstract |
In the current research project, we investigated the pathophysiological significance of big mitogen-acivated protein kinase 1 in diabetic nephropathy for the development of molecular-targeted drugs.
1)In cultured rat mesangial cells; big mitogen-activated protein kinase 1 (BMK1) was activated by high glucose stimulation in a time and concentration-dependent manner. Protein kinase C and c-Src were suggested to be involved in BMK1 activation. From the results of transfection with dominant-negative MEKS to the cells, BMK1 was suggested to be involved in mesangial cell proliferation, which is one of the causes of diabetic nephropathy.
2)In type 2 diabetic rat model OLETF, BMKI was activated in the glomeruli at 52 weeks of age with apparent proteinuria. In addition, BMK1 was also activated in the kidney of rat models of salt-sensitive hypertension (Dahl rats) and aldosterone-infused rats. From these results, it was suggested that BMKI activation is involved not only in diabetic nephropathy but also in hypertensive kidney injury.
3)In disease model rats, treatment with antioxidants or angiotensin II receptor antagonist ameliorated renal injury with concomitant decrease in BMK1 activity. Therefore, it was suggested that BMK1 is involved in the progression of several renal diseases, such as diabetic nephropathy and other etiologies.
4) In circulation, laminar fluid shear stress is atheroprotective whereas turbulent fluid shear stress is prone to atherosclerotic. In human umbilical vein endothelial cells (HUVEC), laminar fluid shear stress inhibited tumor necrosis factor alpha-induced c-Jun N-terminal kinase (JNK) activation. As a molecular mechanism of this inhibition, BMK1 activation was suggested to be a negative regulator of JNK activation.
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