| Project/Area Number |
16590440
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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 |
Applied pharmacology
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| Research Institution | Osaka City University |
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Principal Investigator |
MIURA Katsuyuki Osaka City University, Med Sch, Dept Appl Pharmacol Ther, Professor, 大学院・医学研究科, 教授 (00183624)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | renal fibrosis / nuclear factor kappaB / nephrotoxicity / macrophage / ヘムオキシゲナーゼ / NF-kappaB / クルクミン |
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| Research Abstract |
We previously reported that inhibition of proinflammatory transcription factor, nuclear factor kappaB (NF-κB) attenuated renal interstitial inflammation and fibrosis elicited by calcineurin inhibitors, cyclosporin A and tacrolimus. The existence of interstitial inflammatory responses are not unique to drug-induced renal fibrosis but are common to any form of renal fibrosis. Blockade of this inflammatory response led to inhibition of renal fibrosis. Oral adsorbent that inhibited intestinal absorption of uremic toxin attenuated renal NF-kB activation and inflammation that resulted in inhibition of renal fibrosis in chronic uremic model following subtotal nephrectomy. Curcumin attenuated renal inflammation and subsequently ameliorated renal fibrosis following unilateral ureteral obstruction. We showed that inhibition of NF-kB is a likely mechanism. We also showed that inhibition of enhanced expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage infiltration within the kidney are possible downstream mechanisms by which these drugs acted.
As Rho-kinase play a role in inflammation, we next elucidated the role of Rho-kinase in renal inflammation and fibrosis elicited by two different maneuver, tacrolimus administration and ureteral occlusion. Rho-kinase inhibitor, fasudil partially attenuated renal inflammation following ureteral occlusion but not that observed in chronic tacrolimus nephrotoxicity. These results may indicate that Rho-kinase is not a common mechanism by which renal fibrosis develops. Further study is required to clarify the precise role of Rho-kinase in the pathogenesis of renal fibrosis.
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