2007 Fiscal Year Final Research Report Summary
Role of collagenases and gelatinases in renal injury and their, therapeutic applications
| Project/Area Number |
17590844
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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 | Keio University |
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Principal Investigator |
SASAMURA Hiroyuki Keio University, School of Medicine, Assistant Professor (00235293)
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| Co-Investigator(Kenkyū-buntansha) |
OKADA Yasunori , School of Medicine, Professor (00115221)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Collagenase / Gelatinase / Renal iniury / Nephrotic syndrome |
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| Research Abstract |
Objectives : Hypertensive nephrosclerosis is the leading cause of end-stage renal disease in the US and other countries. Although glomerulosclerosis occurs because of the abnormal accumulation of extracellular matrix components, the role of the matrix-degrading metalloproteinases (MMPs) in the pathogenesis of glomerular injury remains unclear. To examine potential roles of MMP-9 in the pathogenesis of hypertension and glomerulosclerosis, we examined the effects of MMP-9 deletion on blood pressure and disease development in a mouse model of glomerulosclerosis.
Methods: Mice with targeted deletion of MMP-9 (MMP-9 KO) and their wild-type controls were divided into 8 groups and injected intravenously with adriamycin (20 mg/kg) to elicit glomerulosclerosis. The mice were sacrificed 4 weeks or 8 weeks after injection, and the levels of albuminuria, blood urea nitrogen(BUN)/creatinine, and degree of glomerular injury and type IV collagen expression were analyzed. Oxidative stress was estimated by the measurement of urine 8-hydroxydeoxyguanosine (8-OHdG) levels.
Results : No signs of hypertension, albuminuria or renal injury were seen in the MMP-9 KO mice at baseline. Treatment with adriamycin caused severe proteinuria in all mice, but the levels were attenuated in the MMP-9 KO mice compared to controls at 4 weeks (2.13+0.93 vs 5.71+1.40 mg/mgCr, p<0.05). At 8 weeks, a decrease in PAS-positive mesangial matrix deposition (27+3 vs 37+3, p<0.05), and type IV collagen immunostaining(36.3+4 vs 56.3+5, p<0.05) was seen in the MMP-9 KO mice compared to controls. 8-OHdG levels were increased in all the adriamycin-treated rats but the levels were unaffected by MMP-9 deletion. Blood pressure was unchanged in the different groups. Conclusions : These results suggest that the absence of MMP-9 attenuates glomerular lesions and albuminuria by a mechanism independent of changes in blood pressure or oxidative stress, consistent with a pathogenetic role for MMPs in glomerulosclerosis.
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