Pravastatin improves renal ischemia–reperfusion injury by inhibiting the mevalonate pathway
2008; Elsevier BV; Volume: 74; Issue: 5 Linguagem: Inglês
10.1038/ki.2008.210
ISSN1523-1755
AutoresSatoru Sharyo, Naoko Yokota‐Ikeda, Miyuki Mori, Kazuyoshi Kumagai, Kazuyuki Uchida, Katsuaki Ito, Melissa J. Burne-Taney, Hamid Rabb, Masahiro Ikeda,
Tópico(s)Trace Elements in Health
ResumoStatins are known to lessen the severity of renal ischemia-reperfusion injury. The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model. Treatment of mice with pravastatin, a widely used statin, improved renal function after renal ischemia-reperfusion without lowering the plasma cholesterol level. Administration of pravastatin with mevalonate, a product of HMG-CoA reductase, eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism. In hypercholestrolemic apolipoprotein E knockout mice with reduced HMG-CoA reductase activity; the degree of injury was less severe than in control mice, however, there was no protective action of pravastatin on renal injury in the knockout mice. Treatment with a farnesyltransferase inhibitor (L-744832) mimicked pravastatin's protective effect but co-administration with the statin provided no additional protection. Both pravastatin and L-744832 inhibited the injury-induced increase in plasma IL-6 concentration to a similar extent. Our results suggest the protective effect of pravastatin on renal ischemia-reperfusion injury is mediated by inhibition of the mevalonate-isoprenoid pathway independent of its lipid lowering action. Statins are known to lessen the severity of renal ischemia-reperfusion injury. The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model. Treatment of mice with pravastatin, a widely used statin, improved renal function after renal ischemia-reperfusion without lowering the plasma cholesterol level. Administration of pravastatin with mevalonate, a product of HMG-CoA reductase, eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism. In hypercholestrolemic apolipoprotein E knockout mice with reduced HMG-CoA reductase activity; the degree of injury was less severe than in control mice, however, there was no protective action of pravastatin on renal injury in the knockout mice. Treatment with a farnesyltransferase inhibitor (L-744832) mimicked pravastatin's protective effect but co-administration with the statin provided no additional protection. Both pravastatin and L-744832 inhibited the injury-induced increase in plasma IL-6 concentration to a similar extent. Our results suggest the protective effect of pravastatin on renal ischemia-reperfusion injury is mediated by inhibition of the mevalonate-isoprenoid pathway independent of its lipid lowering action. Acute kidney injury (AKI), previously referred to as acute renal failure, is a common clinical syndrome resulting from a rapid reduction of glomerular filtration rate. AKI has been reported to occur in approximately 5% of hospitalized patients and 30–50% of patients in intensive care units. Despite the significant improvements in supportive care, the mortality and morbidity associated with AKI continue to be alarmingly high over the past three decades.1.Lameire N. Van Biesen W. Vanholder R. Acute renal failure.Lancet. 2005; 365: 417-430Abstract Full Text Full Text PDF PubMed Scopus (726) Google Scholar,2.Devarajan P. Update on mechanisms of ischemic acute kidney injury.J Am Soc Nephrol. 2006; 17: 1503-1520Crossref PubMed Scopus (732) Google Scholar,3.Xue J.L. Daniels F. Star R.A. et al.Incidence and mortality of acute renal failure in medicare beneficiaries, 1992–2001.J Am Soc Nephrol. 2006; 17: 1135-1142Crossref PubMed Scopus (581) Google Scholar A major reason for this is a lack of specific pharmacological interventions against AKI.1.Lameire N. Van Biesen W. Vanholder R. Acute renal failure.Lancet. 2005; 365: 417-430Abstract Full Text Full Text PDF PubMed Scopus (726) Google Scholar The mevalonate pathway mediates the sequential biochemical reactions leading to the synthesis of cholesterol.4.Goldstein J.L. Brown M.S. Regulation of the mevalonate pathway.Nature. 1990; 343: 425-430Crossref PubMed Scopus (4356) Google Scholar,5.Palinski W. Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.J Am Soc Nephrol. 2002; 13: 1673-1681Crossref PubMed Scopus (101) Google Scholar Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, statins, block the conversion of HMG-CoA to mevalonate, which is a rate-determining step in the mevalonate pathway, resulting in decreased cholesterol production.6.Tsujita Y. Discovery and development of hypolipidemic drug, pravastatin sodium.Tiss Cult Res Commun. 1993; 12: 279-289Google Scholar As hyperlipidemia causes tissue injury through direct toxic effects of lipids on cells and a formation of intratissue atherosclerosis, statins are widely used to lower plasma cholesterol levels in hyperlipidemic patients.5.Palinski W. Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.J Am Soc Nephrol. 2002; 13: 1673-1681Crossref PubMed Scopus (101) Google Scholar,7.Simes R.J. Marschner I.C. Hunt D. et al.Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial. To what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels?.Circulation. 2002; 105: 1162-1169Crossref PubMed Scopus (235) Google Scholar,8.Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389Abstract PubMed Scopus (10869) Google Scholar,9.Shepherd J. Cobbe S.M. Ford I. et al.Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.N Engl J Med. 1995; 333: 1301-1307Crossref PubMed Scopus (7283) Google Scholar,10.The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5239) Google Scholar Blocking cholesterol synthesis was thought to be the primary statins' mechanism of action. However, reports about plasma cholesterol-independent tissue-protective effects of statins have been increasing, and it is now recognized that statins have clinical benefits that appear to be greater than those one would expect from improving the lipid profile alone.5.Palinski W. Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.J Am Soc Nephrol. 2002; 13: 1673-1681Crossref PubMed Scopus (101) Google Scholar,8.Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389Abstract PubMed Scopus (10869) Google Scholar,9.Shepherd J. Cobbe S.M. Ford I. et al.Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.N Engl J Med. 1995; 333: 1301-1307Crossref PubMed Scopus (7283) Google Scholar,10.The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5239) Google Scholar,11.Rosenson R.S. Tangney C.C. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction.JAMA. 1998; 279: 1643-1650Crossref PubMed Scopus (962) Google Scholar,12.Maron D.J. Fazio S. Linton M.F. Current perspectives on statins.Circulation. 2000; 101: 207-213Crossref PubMed Scopus (1051) Google Scholar The plasma cholesterol-independent tissue-protective effects of statins are thought to be mediated by their immunomodulatory and anti-inflammatory effects that relate to statin's ability to block the synthesis of important intermediate products, including the isoprenoids in the mevalonate pathway.5.Palinski W. Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.J Am Soc Nephrol. 2002; 13: 1673-1681Crossref PubMed Scopus (101) Google Scholar,13.Laufs U. Liao J.K. Direct vascular effects of HMG-CoA reductase inhibitors.Trends Cardiovasc Med. 2000; 10: 143-148Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar,14.Kwak B. Mulhaupt F. Myit S. et al.Statins as a newly recognized type of immunomodulator.Nat Med. 2000; 6: 1399-1402Crossref PubMed Scopus (1196) Google Scholar,15.Diomede L. Albani D. Sottocorno M. et al.In vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products.Arterioscler Thromb Vasc Biol. 2001; 21: 1327-1332Crossref PubMed Scopus (197) Google Scholar Renal ischemia–reperfusion (I/R) injury is an important cause for AKI. There is growing evidence that intrarenal inflammation is involved in renal I/R injury using in vitro and in vivo models, and therefore intrarenal inflammation is an attractive target for the development of drug therapies for AKI.16.Ysebaert D.K. De Greef K.E. Vercauteren S.R. et al.Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury.Nephrol Dial Transplant. 2000; 15: 1562-1574Crossref PubMed Scopus (293) Google Scholar,17.Rabb H. Daniels F. O'Donnell M. et al.Pathophysiological role of T lymphocytes in renal ischemia–reperfusion injury in mice.Am J Physiol Renal Physiol. 2000; 279: F525-F531PubMed Google Scholar,18.Ikeda M. Prachasilchai W. Burne-Taney M.J. et al.Ischemic acute tubular necrosis models and drug discovery: a focus on cellular inflammation.Drug Discov Today. 2006; 11: 364-370Crossref PubMed Scopus (31) Google Scholar Given that statins have immunomodulatory effects, they would be expected to protect against renal I/R injury. Thus far, several groups have tested the protective effects of statins, including pravastatin,19.Joyce M. Kelly C. Winter D. et al.Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates renal injury in an experimental model of ischemia–reperfusion.J Surg Res. 2001; 101: 79-84Abstract Full Text PDF PubMed Scopus (77) Google Scholar cerivastatin,20.Gueler F. Rong S. Park J.K. et al.Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.J Am Soc Nephrol. 2002; 13: 2288-2298Crossref PubMed Scopus (125) Google Scholar,21.Yokota N. O'Donnell M. Daniels F. et al.Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia–reperfusion injury.Am J Nephrol. 2003; 23: 13-17Crossref PubMed Scopus (81) Google Scholar and atorvastatin,22.Sabbatini M. Pisani A. Uccello F. et al.Atorvastatin improves the course of ischemic acute renal failure in aging rats.J Am Soc Nephrol. 2004; 15: 901-909Crossref PubMed Scopus (65) Google Scholar on experimental renal I/R injury, and these data have consistently shown that statins improve the course of the injury. However, it is not yet clear whether the protective action of statins on renal I/R injury is mediated by their lipid-lowering action or the inhibition of the mevalonate pathway in any in vivo studies. To clarify the mechanism of statin's action in vivo, this study examined the effect of mevalonate on the protective effect of pravastatin from renal I/R injury using a mouse model. The renoprotective effect of pravastatin was also evaluated using apolipoprotein E-deficient mice (ApoE−/−) that is known to exhibit hypercholesterolemia.23.Kuipers F. van Ree J.M. Hofker M.H. et al.Altered lipid metabolism in apolipoprotein E-deficient mice dose not affect cholesterol balance across the liver.Hepatology. 1996; 24: 241-247Crossref PubMed Google Scholar,24.Moghadasian M.H. McManus B.M. Nguyen L.B. et al.Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans.FASEB J. 2001; 15: 2623-2630Crossref PubMed Scopus (119) Google Scholar Furthermore, to dissect further the mechanism of statin's renoprotection, we examined whether prenylation inhibitors, including L-744832 and GGTI-2133, protected mice against renal I/R injury. Our results indicate that the protective effect of pravastatin on renal I/R injury is dependent on the mevalonate–isoprenoid pathway, but independent of its lipid-lowering action. First, we confirmed the protective effect of pravastatin on renal I/R injury. The mice were divided into three groups. Control group was treated with vehicle, low-dose group was given 50 mg per kg body weight of pravastatin and high-dose group was given 150 mg per kg body weight of pravastatin. As shown in Figure 1a, although no significant effect was observed in the low-dose group at any time points and in the high-dose group at 48 and 72 h after I/R, plasma creatinine level of the high-dose group was significantly lower than the control group at 24 h after I/R. Histopathological analysis with periodical acid-Schiff (PAS) staining revealed that I/R caused cast formation in tubules, tubular dilatation, and leukocyte infiltration in the outer medulla (Figure 1b). Pravastatin ameliorated these pathological changes (Figure 1c). As the histopathological changes were semiquantified by the measurement of PAS-positive area (Figure 1d), the improvement by pravastatin was dose dependent. These data clearly collaborated with the previous observation that pravastatin had protective effect in a rat renal I/R model.19.Joyce M. Kelly C. Winter D. et al.Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates renal injury in an experimental model of ischemia–reperfusion.J Surg Res. 2001; 101: 79-84Abstract Full Text PDF PubMed Scopus (77) Google Scholar Next, we studied the effect of mevalonate, a product of HMG-CoA reductase, on renal I/R injury. The mice were divided into four groups: control group (vehicle treatment and sham operation); mevalonate treatment and sham operation group; vehicle treatment and I/R group; mevalonate treatment and I/R group. Figure 2 summarizes the data for plasma total cholesterol and creatinine concentrations. Mevalonate tended to increase the plasma total cholesterol in sham-operated mice and significantly increased it in I/R-operated mice. Approximately 40% of administered mevalonate has been reported to be eliminated into urine.25.McNamara D.J. Ahrens Jr, E.H. Parker T.S. Role of the kidneys in the metabolism of plasma mevalonate. Studies in humans and in rhesus monkeys.J Clin Invest. 1985; 76: 31-39Crossref PubMed Scopus (17) Google Scholar Therefore, this increase in cholesterol may be explained by the impairment of mevalonate excretion into the urine by I/R injury, thereby increasing blood mevalonate concentration with consecutive increase in the cholesterol synthesis in liver. I/R significantly increased plasma creatinine level at 24 h after the operation, and this increase was significantly enhanced by the pretreatment of mice with mevalonate. These raise a possibility that mevalonate worsens the renal I/R injury. The effect of mevalonate on the renoprotective action of pravastatin was examined. The mice were divided into three groups: control group (both vehicles for pravastatin and mevalonate treatment); pravastatin and vehicle for mevalonate treatment group; pravastatin and mevalonate treatment group. Plasma cholesterol levels 24 h after I/R did not differ between the three groups (Figure 3a). At 24 h after I/R, plasma creatinine concentration in the pravastatin and vehicle for mevalonate treatment group was significantly lower than that in the control group. In contrast, the protective effect of pravastatin from renal I/R injury was not observed in the pravastatin and mevalonate treatment group. These data suggest that the renoprotective effect of pravastatin is mediated by an inhibition of the mevalonate pathway. Apolipoprotein E knockout mice (ApoE−/−) have been reported to exhibit hypercholesterolemia insensitive to statins and a lower activity of HMG-CoA reductase.23.Kuipers F. van Ree J.M. Hofker M.H. et al.Altered lipid metabolism in apolipoprotein E-deficient mice dose not affect cholesterol balance across the liver.Hepatology. 1996; 24: 241-247Crossref PubMed Google Scholar,24.Moghadasian M.H. McManus B.M. Nguyen L.B. et al.Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans.FASEB J. 2001; 15: 2623-2630Crossref PubMed Scopus (119) Google Scholar,26.Scalia R. Gooszen M.E. Jones S.P. et al.Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice.Circulation. 2001; 103: 2598-2603Crossref PubMed Scopus (196) Google Scholar,27.Monetti M. Canavesi M. Camera M. et al.Rosuvastatin displays anti-atherothrombotic and anti-inflammatory properties in apoE-deficient mice.Pharmacol Res. 2007; 55: 441-449Crossref PubMed Scopus (66) Google Scholar We used these mice and evaluated the effect of hyperlipidemia on renal I/R injury. Mean±s.e. values of the plasma total cholesterol concentration 24 h after sham operation or I/R were 78.0±8.5 (sham) and 137.8±33.9 mg/100 ml (I/R) for the genetic control (C57BL/6J) mice (n=4), and 842.3±129.4 (sham) and 776.5±51.6 mg/100 ml (I/R) for ApoE−/− (n=4), respectively. Mean±s.e. values of the creatinine concentrations 24 h after sham operation and I/R were 0.1±0.01 (sham) and 2.1±0.2 mg/100 ml (I/R) for the control mice, and 0.1±0.01 (sham) and 2.1±0.5 mg/100 ml (I/R) for ApoE−/−, respectively. These values were not significantly different between the control mice and ApoE−/−. Figure 4 shows the results from histopathological analysis with PAS staining. I/R dramatically caused cast formation in the control mice, whereas the change in ApoE−/− was somewhat reduced. The PAS-positive area in ApoE−/− after I/R was significantly smaller than that in the control mice. These data show that hyperlipidemia of ApoE−/− does not worsen the renal I/R injury but seems to rather weaken it. We checked the protective effect of pravastatin on renal I/R injury in ApoE−/−. Figure 5 summarizes the data for plasma total cholesterol and creatinine concentrations. In the control mice, increase in plasma total cholesterol level by renal I/R was observed. On the contrary, I/R decreased plasma total cholesterol concentration in ApoE−/−. These changes in response to I/R were not affected by the treatment with pravastatin. The mechanism underlying the I/R-induced plasma cholesterol changes in both the control mice and ApoE−/− is not clear at present. In the control mice, renal function after I/R was significantly improved by the treatment with pravastatin compared with mice treated with vehicle (Figure 5c). This renal protective action of pravastatin was not seen in ApoE−/− (Figure 5d). It is known that the mevalonate pathway regulates the biosynthesis of cholesterol as well as isoprenoids including farnesyl pyrophosphate and geranylgeranyl pyrophosphate. We thus evaluated the renoprotective effects of L-744832 (farnesyltransferase inhibitior) and GGTI-2133 (geranylgeranyl transferase I inhibitior) on renal I/R injury.28.Kohl N.E. Omer C.A. Conner M.W. et al.Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice.Nat Med. 1995; 1: 792-797Crossref PubMed Scopus (501) Google Scholar,29.Johnson T.E. Zhang X. Bleicher K.B. et al.Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone.Toxicol Appl Pharmacol. 2004; 200: 237-250Crossref PubMed Scopus (108) Google Scholar L-744832 and GGTI-2133 were administered to mice just after I/R and plasma creatinine levels were measured 24 h after I/R (Figure 6a). Serum creatinine level in L-744832 treatment group was significantly lower than that of vehicle control group (Figure 6a). In contrast, GGTI-2133 had no significant effect on the increase in plasma creatinine concentration after I/R. To examine whether the effect of L-744832 resulted from the inhibition of the mevalonate pathway, we compared the effect of treatment with L-744832 alone with that of combination of L-744832 and pravastatin on I/R-induced dysfunction in normal mice. As shown in Figure 6b, no significant additive effect of the coadministration was observed, indicating that two drugs share the same pathway. Interleukin-6 is primarily involved in the regulation of inflammation.30.Patel N.S. Chatterjee P.K. Di Paola R. et al.Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion.J Pharmacol Exp Ther. 2005; 312: 1170-1178Crossref PubMed Scopus (141) Google Scholar Furthermore, serum IL-6 level is reported to increase after renal I/R.31.Kielar M.L. John R. Bennett M. et al.Maladaptive role of IL-6 in ischemic acute renal failure.J Am Soc Nephrol. 2005; 16: 3315-3325Crossref PubMed Scopus (174) Google Scholar To confirm whether the pravastatin's renoprotection is mediated by its anti-inflammatory effect and L-744832 has a similar effect to pravastatin on serum IL-6 level or not, we measured serum IL-6 levels 24 h after I/R in mice treated with pravastatin or L-744832. Serum IL-6 concentration in mice subjected to I/R was significantly higher than that in intact mice. When mice were treated with pravastatin or L-744832, significantly lower serum IL-6 levels were observed compared with that in mice treated with vehicle (Figure 7). This study clearly showed that pravastatin, a widely used statin, protected normal mice from renal I/R injury without any reduction in plasma cholesterol level. This renoprotective effect of pravastatin was diminished by the coadministration of mevalonate with pravastatin. When we used ApoE−/− that had a 10-times higher plasma total cholesterol concentration compared with that of their genetic control and had been shown to exhibit a reduced activity of HMG-CoA reductase,23.Kuipers F. van Ree J.M. Hofker M.H. et al.Altered lipid metabolism in apolipoprotein E-deficient mice dose not affect cholesterol balance across the liver.Hepatology. 1996; 24: 241-247Crossref PubMed Google Scholar,24.Moghadasian M.H. McManus B.M. Nguyen L.B. et al.Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans.FASEB J. 2001; 15: 2623-2630Crossref PubMed Scopus (119) Google Scholar pravastatin had no effect on renal I/R injury. Treatment with mevalonate alone worsened the degree of renal I/R injury. Treatment with L-744832, an isoprenylation inhibitor, significantly ameliorated renal dysfunction after I/R. The combination of pravastatin and L-744832 did not further improve renal dysfunction after I/R, compared with treatment with L-744832 alone. Pravastatin as well as L-744832 inhibited I/R-induced increase in plasma IL-6 concentration to a similar extent. Together, these data strongly suggest that the inhibition of the mevalonate–isoprenoid pathway, which leads to anti-inflammation, is important for the renoprotective action of pravastatin. Moreover, the lipid-lowering action of pravastatin is unlikely to be related to its protective effect on renal I/R injury. Biologically important products other than cholesterol in the mevalonate pathway are dolichols, ubiquinone, and the isoprenoids, including farnesyl pyrophosphate and geranylgeranyl pyrophosphate.4.Goldstein J.L. Brown M.S. Regulation of the mevalonate pathway.Nature. 1990; 343: 425-430Crossref PubMed Scopus (4356) Google Scholar,5.Palinski W. Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.J Am Soc Nephrol. 2002; 13: 1673-1681Crossref PubMed Scopus (101) Google Scholar Isoprenoids are known to play an important role in the post-translational modification of G proteins such as Ras, Rho, and Rab, for their proper intracellular localization.5.Palinski W. Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis.J Am Soc Nephrol. 2002; 13: 1673-1681Crossref PubMed Scopus (101) Google Scholar,13.Laufs U. Liao J.K. Direct vascular effects of HMG-CoA reductase inhibitors.Trends Cardiovasc Med. 2000; 10: 143-148Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar The protein isoprenylation reaction is catalyzed by farnesyl or geranylgeranyl transferase. In this study, the treatment with L-744832, a farnesyl transferase inhibitor,28.Kohl N.E. Omer C.A. Conner M.W. et al.Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice.Nat Med. 1995; 1: 792-797Crossref PubMed Scopus (501) Google Scholar significantly improved the renal deficit after I/R. On the other hand, GGTI-2133, a geranylgeranyl transferase I inhibitor,29.Johnson T.E. Zhang X. Bleicher K.B. et al.Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone.Toxicol Appl Pharmacol. 2004; 200: 237-250Crossref PubMed Scopus (108) Google Scholar had not significant effect on renal I/R injury. Recently, chaetomellic acid A, a farnesyltransferase inhibitor, was also reported to produce protection against I/R-induced renal dysfunction.32.Sabbatini M. Santillo M. Pisani A. et al.Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury.Am J Physiol Renal Physiol. 2006; 290: F1408-F1415Crossref PubMed Scopus (39) Google Scholar These data suggest that protein farnesylation is involved in pathobiology of renal I/R injury, and this leads to the development of specific pharmacological interventions. We demonstrate here that serum IL-6 level was significantly increased after renal I/R, and this increase was prevented by pravastatin or L-744832 treatment. IL-6 is a pleiotropic cytokine and a major regulator of inflammation.30.Patel N.S. Chatterjee P.K. Di Paola R. et al.Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion.J Pharmacol Exp Ther. 2005; 312: 1170-1178Crossref PubMed Scopus (141) Google Scholar Growing evidence suggests that IL-6 is a critical contributor to renal I/R injury. In IL-6 knockout mice, the degree of renal I/R injury was less severe compared with that of the genetic control mice.30.Patel N.S. Chatterjee P.K. Di Paola R. et al.Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion.J Pharmacol Exp Ther. 2005; 312: 1170-1178Crossref PubMed Scopus (141) Google Scholar Normal mice administered a monoclonal antibody against IL-6 were resistant to renal I/R injury.30.Patel N.S. Chatterjee P.K. Di Paola R. et al.Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion.J Pharmacol Exp Ther. 2005; 312: 1170-1178Crossref PubMed Scopus (141) Google Scholar,31.Kielar M.L. John R. Bennett M. et al.Maladaptive role of IL-6 in ischemic acute renal failure.J Am Soc Nephrol. 2005; 16: 3315-3325Crossref PubMed Scopus (174) Google Scholar Increased production of IL-6 in the ischemic kidney originated largely from macrophages that infiltrated into the outer medulla.31.Kielar M.L. John R. Bennett M. et al.Maladaptive role of IL-6 in ischemic acute renal failure.J Am Soc Nephrol. 2005; 16: 3315-3325Crossref PubMed Scopus (174) Google Scholar Resistance of IL-6 knockout mice to renal I/R injury was reduced by the reconstitution of IL-6 knockout mice with bone marrow from wild-type mice.31.Kielar M.L. John R. Bennett M. et al.Maladaptive role of IL-6 in ischemic acute renal failure.J Am Soc Nephrol. 2005; 16: 3315-3325Crossref PubMed Scopus (174) Google Scholar Moreover, a genetic heme oxygenase-1 deficiency in mice increased the sensitivity to renal I/R injury, and this increase was lowered by the treatment of mice with a monoclonal antibody against IL-6.33.Tracz M.J. Juncos J.P. Croatt A.J. et al.Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia.Kidney Int. 2007; 72: 1073-1080Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Hence, the renoprotective effects of paravastatin and L-744832 against I/R injury may be mediated through the suppression of IL-6 production. We note that Xue et al.34.Xue X. Lai K.T. Huang J.F. et al.Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor tipifarnib.J Pharmacol Exp Ther. 2006; 317: 53-60Crossref PubMed Scopus (31) Google Scholar recently reported that pretreatment with tipifarnib, a farnesyl transferase inhibitor, resulted in a significant inhibition of IL-6 production in a murine model of LPS-induced inflammation. In this study, pravastatin and L-744832 could not completely protect mice against renal I/R injury. Similar partial effects of other statins including cerivastatin and atorvastatin on renal I/R injury have been reported.20.Gueler F. Rong S. Park J.K. et al.Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.J Am Soc Nephrol. 2002; 13: 2288-2298Crossref PubMed Scopus (125) Google Scholar,21.Yokota N. O'Donnell M. Daniels F. et al.Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia–reperfusion injury.Am J Nephrol. 2003; 23: 13-17Crossref PubMed Scopus (81) Google Scholar,22.Sabbatini M. Pisani A. Uccello F. et al.Atorvastatin improves the course of ischemic acute renal failure in aging rats.J Am Soc Nephrol. 2004; 15: 901-909Crossref PubMed Scopus (65) Google Scholar Although the exact reason for the insufficient effect of statins is not clear at present, this might be explained by an inhibitory activity of statins on a mammalian target of rapamycin (mTOR) pathway. Recently, Finlay et al.35.Finlay G.A. Malhowski A.J.
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