2006 Fiscal Year Final Research Report Summary
The potential of antisense oligonucleotide inhibiting chronic rejection of renal allografts
| Project/Area Number |
15390498
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | FUJITA HEALTH UNIVERSITY |
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Principal Investigator |
HOSHINAGA Kiyotaka FUJITA HEALTH UNIVERSITY, School of Medicine, Professor, 医学部, 教授 (30229174)
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| Co-Investigator(Kenkyū-buntansha) |
SHIROKI Ryoichi FUJITA HEALTH UNIVERSITY, School of Medicine, Associate Professor, 医学部, 助教授 (70226330)
KUSAKA Mamoru FUJITA HEALTH UNIVERSITY, School of Medicine, Assistant Professor, 医学部, 講師 (40309141)
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| Project Period (FY) |
2003 – 2006
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| Keywords | brain death / ischemia / reperfusion injury / real time PCR / microarray / chronic rejection |
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| Research Abstract |
It has been well documented that two factors, brain death (BD) and ischemia/reperfusion (I/R) injury, have distinct but overlapping adverse influences on the clinical outcome of renal transplantation. We previously established a rat model of renal isografting from brain dead donors. We performed genomic expression profiling with a microarray to identify genes that were upregulated or downregulated by BD and/or I/R injury. Most of those upregulated by BD were genes for adhesion molecules and cytokines, or for chemokines such as Grol and IP-10. Analysis of biological networks demonstrated the activation of specific pathways that were clearly different for BD and I/R injury. The p53 and NFkappaB pathway was involved in the acute response to BD whereas the Myc, Jun, and c-fos pathway was involved in I/R injury. Investigation of secretory protein genes identified LCN2 and SPP1 as candidate genes for biological markers. In clinical study, we performed gene expression profiling using one-hour
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biopsy samples from DCD kidneys and compared with those from living sources. All graft biopsies were performed 1 hour after reperfusion (DCD n=8,LD n=15). The expression profile of 20,173 genes was analyzed. 178 genes were up-regulated and 120 genes down-regulated in DCD kidneys. Expression of Osteopontin, chemokines, adhesion molecule and heat shock proteins was up-regulated in the kidneys from DCD. This is the first demonstration of an analysis of global gene expression using one-hour biopsy samples from DCD kidneys. These results provide new insight into the identification of novel target genes for the development of therapeutics and for determining graft viability of kidneys from DCD. The final study evaluated serum NGAL as a potential specific parameter to predict early functional recovery of transplanted DCD kidneys. In patients undergoing a living-related KTx from a living donor (n=11), serum NGAL level decreased rapidly after KTx, and only in two cases, with serum NGAL levels over 400 ng/ml on post operative day 1 (POD1), as HD required due to DGF. In contrast, all patients undergoing a KTx from a DCD (n=5) required HD due to DGF. Even in these cases, serum NGAL levels decreased rapidly several days after a KTx prior to the recovery of urine output and preceding the decrease in serum creatinine level. The pattern of decline in serum NGAL was biphasic, the decrease after the second peak indicating a functional recovery within the next several days. These data suggest that monitoring of serum NGAL levels may allow us to predict graft recovery and the need for HD after a KTx from a DCD. Less
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Research Products
(10 results)
