| Project/Area Number |
12671034
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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 |
Kidney internal medicine
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| Research Institution | FACULTY OF MEDICINE FUKUI MEDICAL UNIVERSITY |
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Principal Investigator |
KIMURA Hideki FUKUI MEDICAL UNIVERSITY, FACULTY OF MEDICINE, ASSISTANT, 附属病院, 助手 (20283187)
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| Co-Investigator(Kenkyū-buntansha) |
FUJII Hiroshi NIGATA UNIVERSITY,FACULTY OF MEDICINE, ASSISTANT PROFESSOR, 医学部, 助教授 (90165340)
SUZUKI Satoru FUKUI MEDICAL UNIVERSITY,FACULTY OF MEDICINE, ASSISTANT PROFESSOR, 医学部, 助教授 (00206484)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | kidnev / PPAR / Hold-binding nrotein / cell culture / PAI- 1 / GETP / eosmophil / homocvsteine / Immuno histochemistry / Macrophage / Homocysteine |
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| Research Abstract |
1. Investigation on the expression ofLBPs and PPARs in normal and diseased human kidneys.
(1) In normal human kidney, liver type (L-) fatty acid-binding protein (FABP) and heart-type FABP were predominantly localized in cytoplasm of proximal and distal renal tubular epithelial cells (RTEC), respectively. PPAR-α was mainly present in cytoplasm of proximal RTEC and PPAR-γ was present in cytoplasm of distal RTEC and collecting ducts.
(2) As for transplanted kidneys suffering from severe hypoxia, the expressions of L-FABP and PPAR-α were increased in cytoplasm of some proximal RTECs. In interstitial nephritis, nuclear stainings for L-FABP and PPAR-α were found in some proximal RTECs, suggesting the interaction between L-FABP and PPAR-α. Purified L-FABP contained endogenously long-chain fatty acids which can serve as ligands, stimulators for PPAR-α. In interstitial nephritis, PPAR-α was expressed in infiltrating eosinophils but not macrophages. In membranous nephropathy, nuclear staining for
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PPAR-α was more frequent than normal kidney.
2. Investigation on the expression of LBPs and PPARs in human cultured proximal renal tubular epithelial cells.
(1) Indirect immunofluorescence method and immunoblotting revealed that L-FABP and PPAR-α were expressed in human cultured proximal renal tubular epithelial cells. PAI-1 was also expressed in the cultured cells.
(2) PAI-1 antigen was detected in the medium of human cultured proximal renal tubular cells at a concentration of 250-600 ng/mL after the cells were cultured in the medium including several growth factors and bioactive molecules. Addition of hydrocortisone and epinephrine to the basic medium increased the concentration of PAI- 1 in the conditioned medium of the cultured cells. Hypoxia appeared to induce further the expression of PAI-1 in the cells cultured in the growth medium.
3. Analysis of relationships between clinical variables and advanced renal disease and vascular disease.
In hemodialysis patients with high HDL-C status, cholesteryl ester transfer protein (CETP) was a protective factor against vascular disease. A common C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was associated with increased serum levels of homocysteine which causes oxidative stress to endothelial cells. The homozygous mutants (TT genotype) were younger at the induction of hemodialysis and had a shorter duration of dialysis, suggesting that hyperhomocysteinemia may be related to accelerated progression of renal damage and mortality after initiation of dialysis. Among diabetic patients, PAI-1 concentrations in urine were higher in those with severe proteinuria over 1000 mg/gCr than those with microalbuminuria, while plasma PAI-1 levels were unchanged during progression of diabetic nephropathy. Urinary PAI-1 levels were positively associated with urinary NAG and sugar levels. Less
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