2000 Fiscal Year Final Research Report Summary
MOLECULAR MECHANISM OF MESANGIAL CELL DYSFUNCTION DUE TO HYPERGLYCEMIA AND GLOMERULAR HYPERTENSION
| Project/Area Number |
10671063
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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 | SHIGA UNIVERSITY OF MEDICAL SCIENCE |
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Principal Investigator |
HANEDA Masakazu SHIGA UNIVERSITY OF MEDICAL SCIENCE, THIRD DEPARTMENT OF MEDICINE, ASSISTANT PROFESSOR, 医学部, 講師 (60164894)
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| Co-Investigator(Kenkyū-buntansha) |
KOYA Daisuke SHIGA UNIVERSITY OF MEDICAL SCIENCE,THIRD DEPARTMENT OF MEDICINE, RESEARCH ASSOCIATES, 医学部, 助手 (70242980)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Diabetic nephropathy / Mesangial cells / Stretch stress / extracellular signal-regulated kinase (ERK) / extracellular matrix protein / TGF-β / cGMP / cAMP |
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| Research Abstract |
Hyperglycemia and glomerular hypertension are considered to be main factors responsible for the development of diabetic nephropathy. Although both factors were found to cause mesangial cell dysfunction, the precise mechanisms have not been fully elucidated yet. In the present study, we clearly demonstrated that mechanical stretch due to glomerular hypertension was able to activate extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) through the activation of protein tyrosine kinase, to increase DNA binding activity of AP-1, and thus to enhance the expression of TGF-β and fibronectin (FN) in mesangial cells. An inhibitor of MEK was able to inhibit stretch-induced increase in DNA binding activity of AP-1 and enhancement of TGF-β and FN production. Since we found that hyperglycemia could activate ERK in protein kinase C (PKC)-dependent manner, the mechanism of ERK activation by both factors seems to be different. Thus, we found the additive effect of hyperglycemia and stretch stress on ERK activation and FN production. Furthermore, we found that the agents which could increase cellular cAMP or cGMP were able to prevent stretch-induced activation of ERK and enhancement of FN production. These results indicate that ERK plays a key role in the development of mesangial cell dysfunction under both hyperglycemia and glomerular hypertension through different mechanisms.
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