Abstract
124 Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, inhibits de novo purine synthesis which results in decreased mannosylation of adhesion molecule, some of which play important roles in ischemia/reperfusion (I/R) injury. It has been successfully used in the prevention of renal allograft rejection. Recently, MMF has also been shown to attenuate I/R injury in an experimental model of rat heart allograft transplant. We hypothesized that MMF might attenuate renal I/R injury by inhibiting osteopontin (OPN) expression. The present study was therefore designed to examinc the therapeutic implication of MMF in renal allograft transplantation. Methods: Both in vitro and in vivo models were performed and Sprague-Dawley rats were used. In in vitro study, kidneys were canulated, harvested and flushed with cold UW solution. Inulin clearance (Cin) was examined one hour after cold ischemia. Results: Rats pretreated with MMF (20 mg/kg, gavage) had significantly higher Cin (214 ± 19 μl/min) than those of rats without treatment (58 ± 7 μl/min, n = 5, p < 0.05). To further explore the possible mechanism of this protective effect, in vivo study was done. Rat I/R injury was made by bilateral renal pedicle clamping for 45 mins., followed by 24 hrs. of reperfusion (n = 7). Western blot analyses of osteopontin (OPN) and intercellular adhesion molecule-1 (ICAM-1) were then conducted in renal cortex using monoclonal and polyclonal antibodies respectively. The results showed that both OPN and ICAM-1 were dramatically up-regulated in the renal cortex (3.8 and 2.5 times respectively compared to sham operated rats). When MMF (20 mg/kg, gavage) was administrated 24hrs. prior to and 4 hrs. after renal I/R (n = 8), OPN expression was significantly attenuated by 35% and ICAM-1 expression was almost completely abolished. Conclusion: 1) MMF provides protection against I/R renal injury; 2) MMF-induced inhibition of OPN and ICAM-1 expression in the I/R injured kidney may be important in reducing the subsequent host inflammatory responses after transplantation; 3) the data provide new insight into the mechanisms through which MMF improves graft function and survival in renal transplantation.
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