The High Expression Of Heme Oxygenase-1 Induced By Simvastatin Attenuates Renal Ischemia-reperfusion Injury

Objective:To investigate the expression levels and the roles of heme oxygenase-1 (HO-1) induced by simvastatin in rat kidneys through the ischemia-reperfusion injury(IRI) model and explore the possible protective mechanism of simvastatin on kidneys.Methods:In brief, for IR injury the left renal pedicle was occluded for 45 minutes, and the contralateral right kidney was removed.40 male healthy Wistar rats were randomized into four experimental groups of 10 animals each:simvastatin group, IR group, HO-1 inhibitor group and sham group. For sham group, the right kidneys were excised merely.24 hours after surgery, blood samples were drawn for measurement of serum urea nitrogen (BUN) and creatinine (Cr) concentrations by an automated method. Moreover, pathologic changes of the kidney was observed under light microscopy by HE stain to evaluate the injuries of renal tubules and the expression levels of HO-1 in rat kidneys were measured by immunohistochemistry meanwhile.Results:1. The comparisons of renal functions among different groupsCompared with sham group, the serum levels of BUN and Cr in other groups were significantly higher than those in sham group (P<0.01), and ZnPP group was the highest, while statin group was the lowest. When comparing with IR group, the BUN and Cr were obviously lower in the statin group (P<0.01), however, the injury of renal functions of IR group was much better than those in ZnPP group (P<0.01).2. The histomorphologic changes of rat kidneysThe renal tubular epithelial cells of IR group became edematous with their brush borders falling off partly or completely. Some renal tubule lumens were dilated, while some of them were filled with casts. All these changes were extremely obvious in distal tubules and collecting tubules. Meanwhile, renal interstitium was infiltrated with inflammatory cells with local bleeding and edema. According to the statin group, the pathological changes were much slighter with lesser casts and inflammatory cells. Among all groups, the injury in ZnPP group was the most severe, whose renal tubules were absolutely destroyed. Conversely, the morphologic changes of kidneys in sham group were almost similar to normal kidneys without edema or inflammation. The renal glomeruli were normal in all groups.3. The pathologic Paller's grades of renal tubulesThe more grades of renal tubules, the more severe of the injuries would be. Compared with sham group, the grades of ZnPP group was the highest (239.70±4.79, P<0.05) and IR group was the second (104.38±5.57, P<0.05), while statin group was lower than both of them (39.51±1.62, both P<0.05). The grades of the sham group was the least, which means the injury was the slightest.4. The expressions and distributions of HO-1 in kidneysThe expressions of HO-1 could be found both in statin group and IR group, which mainly distributed in the epithelial cells of proximal and distal tubules, henle loops and collecting tubules. Moreover, the expression levels of HO-1 were diverse in different locations, the colser to the medulla, the more HO-1 would be. Among all groups, HO-1 was the most in the statin group, and IR group was the second. On the contrary, there was almost no HO-1 in ZnPP group, and little HO-1 was found in sham group.Conclusion:HO-1 was a significant cell protective factor for renal ischemia-reperfusion injury, and simvastatin may attenuates renal ischemia-reperfusion injuries by up-regulating the expression levels of HO-1.