2001 Fiscal Year Final Research Report Summary
Molecular biological study on tacrolimus nephrotoxicity
| Project/Area Number |
12671552
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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 |
Urology
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| Research Institution | Osaka City University |
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Principal Investigator |
NAKATANI Tatsuya Osaka City University Medical School, Associate Professor, 大学院・医学研究科, 助教授 (40183511)
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| Co-Investigator(Kenkyū-buntansha) |
MIURA Katsuyuki Osaka City University Medical School, Professor, 大学院・医学研究科, 教授 (00183624)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Renal transplantation / tacrolimus / tubulo-interstitial fibrosis |
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| Research Abstract |
Tacrolimus has been widely used to prevent acute rejection after organ transplantation including pancreas and kidney since 1989 when it was first applied to liver transplantation. However, its nephrotoxicity is a serious problem. Acute toxicity is characterized by functional renal vasoconstriction and chronic nephrotoxicity includes tubulo-interstitial fibrosis. The present research project was conducted to elucidate the mechanisms of tacrolimus-induced nephrotoxicity. We first found that renal cortical gene expression of endothelin-1 and renin was up-regulated by tacrolimus, suggesting the role of these vasoconstrictor system in the acute nephrotoxicity. In addition, we observed characteristic gene expression profiles induced by tacrolimus treatment by using cDNA microarray. We also obtained new findings on the mechanism of chronic nephrotoxicity. Long-term treatment with tacrolimus of rats on low sodium diet induced macrophage infiltration and tubulo-interstitial fibrosis. These changes were accompanied by an increase in DNA-binding activity of NF-kB, a transcription factor known to be related to inflammatory process. An inhibitor of NF-kB, PDTC effectively blocked NF-kB activity, a macrophage influx and development of tubulo-interstitial fibrosis. These results strongly suggest that activation of NF-kB is involved in the pathogenesis of chronic tacrolimus nephrotoxicity.
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