2004 Fiscal Year Final Research Report Summary
The prevention of acute renal failure through the intervention in the DNA repair system.
| Project/Area Number |
15590846
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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 | HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE |
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Principal Investigator |
HISHIDA Akira HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE, professor, 医学部, 教授 (70111812)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Tatsuo HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE, lecturer, 医学部, 講師 (30200819)
FUJIGAKI Yoshihide HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE, assistant, 医学部, 助手 (20283351)
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| Project Period (FY) |
2003 – 2004
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| Keywords | p21 / p27 / cyclineD1 / cyclinB1 / cisplatin / acute renal failure / p21 antisense / GADD45 |
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| Research Abstract |
In this study, we evaluated the expressions and the roles of proteins involved in cell cycle regulation and DNA repair in cisplatin(CDDP)-induced acute renal failure(ARF). CDDP-induced tubular damage and the increase in serum creatinine (Scr) were observed at day 3 and peaked at day 5. The expressions of cell cycle regulatory proteins(p21, p27, cyclin B1 and cyclin D1) and DNA repair-related proteins(PCNA, GADD 45 and GADD 153) were significantly increased in the outer medulla, reaching peak levels at 3 days after CDDP. Sodium arsenite (SA) attenuated tubular damage and increased Scr at 5 day after CDDP. SA augmented GDDP-induced increment of p27 but suppressed the increased expression of cyclin B1 and cyclin D1. SA-induced attenuation of nephrotoxicity was associated with enhanced expression of PCNA and GADD 153 in damaged tubular cells.
The administration of p21 antisense oligodeoxynucleotide(ODN), which was mainly uptaken by cortical proximal tubule(PT) cells, induced a decrease inn the number of p21-positive PT cells in the cortex and aggravated cortical PT damage, but did not affect these in the outer stripe of outer medulla. The antisense also did not alter Scr level at day 5.
Our findings indicated that (1) proteins related to cell cycle regulation and DNA repair are induced in CDDP nephrotoxicity, (2) the SA-induced attenuation of CDDP nephrotoxicity is associated with increased expression of p27 and decreased expression of cyclin B1 and cyclin D1, they all induce cell cycle arrest at G1/S and G2/M, and (3) enhanced expression of DNA repair-related proteins is also associated with attenuation of CDDP-nephrotoxicity.
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