Abstract:Objectives: To investigate whether atorvastatin can induce heme oxygenase-l (HO-1) expression in rat kidneys to prevent contrast- induced acute kidney injury(CI-AKI) and its related mechanisms. Methods: 48 healthy Sprague-Dawley male rats were randomly divided into the blank control group, model group , atorvastatin group and zinc protoporphyrin IX(ZnPPIX) group. A rat model of CI-AKI was established by intramuscular injection of gentamicin sulfate for 2 days and then intravascular injection of 76% meglumine diatrizoate. Atorvastatin group and ZnPPIX group were pretreated with atorvastatin/ZnPPIX before using meglumine diatrizoate. We detected changes in serum creatinine (Scr) before and after model establishment, measured the interleukin-6(IL-6), monocyte chemotactic protein 1 (MCP-1),malondialdehyde(MDA) and total antioxidant capacity (T- AOC) as well as the protein expression of HO-1, Bax, Bcl-2 in the renal tissue, and analyzed the renal cell apoptosis index(AI). Results: After contrast agent injection, compared with the control group,the SCr of the other three groups were significantly increased and reached the CI-AKI standard, Meanwhile, the inflammatory and oxidative stress markers and AI were also significantly increased. Compared with the model group, in atorvastatin group, the expression of HO-1 protein in renal tissue increased significantly, while the level of inflammation and oxidative stress and both AI and SCr decreased significantly (P<0.05),in ZnPPIX group, the expression of HO-1 protein in renal tissue also increased, but the level of inflammation and oxidative stress and both AI and SCr increased significantly(P<0.05). Conclusion: Atorvastatin can induce expression of HO-1 protein in rat kidney throuh which inhibit the renal inflammation and oxidative stress and cell apoptosis, thereby protecting against CI-AKI.
[1] Gleeson TG,Bulugahapitiya S.Contrast-induced nephropathy[J].AJR Am Roentgenol, 2004,183(6):1673~1689. [2] Gupta R,Birnbaum Y,Uretsky B F.The renal patient with coronary artery disease: current concepts and dilemmas[J].Am Coll Cardiol,2004,44(7):1343~1353. [3] Stacul F,Adam A,Becker C R,et al.Strategies to reduce the risk of contrast-induced nephropathy[J].Am Cardiol,2006,98(6A):59K~77K. [4] Toso A,Maioli M,Leoncini M,et al.Usefulness of atorvastatin (80 mg) in prevention of contrast-induced nephropathy in patients with chronic renal disease[J].Am Cardiol,2010,105(3):288~292. [5] Zarjou A,Agarwal A.Heme oxygenase-1 as a target for TGF-β in kidney disease[J].Semin Nephrol, 2012, 32(3):277~286. [6] 段丙军,黄乐,丁红,等.姜黄素预诱导血红素氧合酶1表达防治对比剂肾病的实验研究[J].中华心血管病杂志,2013,41(2):116~120. [7] Muchova L, Wong RJ, Hsu M,et al.Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection[J].Can Physiol Pharmacol, 2007,85(8):800~810. [8] Stacul F, van der moLen A J,Reimer P,et al. Contrast induced nephropathy: updated ESUR Contrast Media Safety Committee guidelines[J].Eur Radiol,2011,21(12): 2527~2541. [9] Tumlin J,Stacul F,Adam A,et al.Pathophysiology of contrast-induced nephropathy[J].Am Cardiol, 2006,98(6A):14K~20K. [10] Asif A,Preston R A,Roth D.Radiocontrast-induced nephropathy[J].Am Ther, 2003,10(2):137~147. [11] 黄乐,段丙军,丁红,等.姜黄素减轻泛影葡胺引起的大鼠肾小管上皮细胞损伤作用的研究[J].山东医药,2012,52(28):37~39. [12] Romano G,Briguori C,Quintavalle C,et al.Contrast agents and renal cell apoptosis[J].Eur Heart,2008,29(20):2569~ 2576. [13] Patti G,Ricottini E, Nusca A,et al.Short-term, high-dose atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the ARMYDA-CIN atorvastatin for reduction of myocardial damage during angioplasty--contrast- induced nephropathy trial[J].Am Cardiol, 2011,108(1):1~7. [14] Ishikawa K, Maruyama Y. Heme oxygenase as an intrinsic defense system in vascular wall:implication against atherogenesis[J].Atheroscler Thromb,2001,8(3): 63~70. [15] Zou AP,Billington H,Su N,et al.Expression and actions of heme oxygenase in the renal medulla of rats[J].Hypertension,2000,35(8):342~347. [16] Haines DD, Lekli I, Teissier P, et al. Role of haeme oxygenase-1 in resolution of oxidative stress-related pathologies: focus on cardiovascular, lung, neurological and kidney disorders[J].Acta Physiol (Oxf), 2012,204(4): 487~501. [17] Kwok SC, Samuel SP, Handal J,et al.Atorvastatin activates heme oxygenase-1 at the stress response elements[J].Cell Mol Med, 2012,16(2):394~400. [18] HPS2-THRIVE Collaborative Group.HPS2-THRIVE randomized placebo- controlled trial in 25673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment[J].Eur Heart,2013,34:1279~1291.