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- Title
Sirolimus Preserves Initial Function and Does not Delay Renal Allograft Recovery after Reperfusion Injury.
- Authors
Dragun, D.; Nieminen-Kelha, M.; Hoff, U.; Linde, Y.; Markmann, D.; Bräsen, J.-H.; Peters, H.; Neumayer, H.-H.; Budde, K.
- Abstract
Objective: Sirolimus is a novel immunosuppressant with proven antirejection properties. Recent studies implicate antiproliferative and antiangiogenic activities of sirolimus in tumors that were linked to a decrease in VEGF production. Considering that VEGF acts as a survival factor for tubular and endothelial cells, antiangiogenic properties of sirolimus may be detrimental for regeneration after posttransplant reperfusion injury. We tested whether or not putative antiproliferative and antiangiogenic properties of sirolimus render renal allografts more susceptible to posttransplant reperfusion injury and delay allograft recovery. Methods: We employed F344-to-Lew rat low-responder model where renal grafts were 2-hours cold preserved in UW solution and transplanted with an average 30 min anastomosis time. Therapeutic trough level was achieved in recipients after 3 mg/kg loading and daily 1.5 mg/kg maintenance sirolimus dose administered by gavage. Grafts were harvested 1, 2, 5 and 7 days after transplantation for functional, morphological and gene expression studies. Results: Beginning at day 1 posttransplant, sirolimus treated animals did not exhibit worsening in creatinin clearance or higher histological tubular damage score. Functional integrity of tubular cells was preserved in sirolimus group as demonstrated by diminished low-molecular weight proteinuria and improved urine concentrating capacity. There was no difference in the PCNA tubular epithelial cell positivity between groups at any time point studied, implying that sirolimus did not inhibit epithelial regeneration. In congruence with these results, there was no epithelial dedifferentiation in sirolimus group as vimentin was not induced. Posttransplant reperfusion injury induced 2-fold decrease of VEGF mRNA in control animals compared to basal conditions. Sirolimus treatment up-regulated VEGF mRNA beyond the level observed in native kidneys. The expression of VEGFR-2 was influenced in the same manner. The increased expression of VEGF was localized to tubular epithelial cells of the cortex and outer medulla in sirolimus group. Furthermore, sirolimus treatment resulted in reduced inflammatory response comprised as significantly decreased infiltration with effector cells: His-48+ granulocytes and ED-1+ monocytes. All sirolimus mediated effects persisted during the time course of the study. We obtained no significant differences in peritubular capillary density as measured by RECA, PECAM-1 and eNOS expression. Conclusions: Sirolimus does not act antiangiogenic during posttransplant reperfusion injury of the kidney. VEGF and VEGF-R2 upregulation observed in sirolimus treated animals may provide antiinflammatory signals and do not delay recovery of renal allografts after reperfusion injury.
- Subjects
RAPAMYCIN; IMMUNOSUPPRESSIVE agents; VASCULAR endothelial growth factors; RETICULO-endothelial system; REPERFUSION injury; KIDNEY diseases
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p308
- ISSN
1420-4096
- Publication type
Article