肾脏急性缺血再灌注损伤的代谢组学研究
|
摘要
目的:通过对急性肾损伤动物模型体内代谢产物进行系统分析,以评估代谢组学能否早期发现急性肾损伤,进一步探索急性肾损伤的发病机制,寻找新的诊断生物标记物和新的治疗方法。方法:建立急性肾损伤缺血再灌注动物模型,收集不同时间点的动物血清和尿液,利用RRLC/Q-TOF-MS的方法对动物体液标本进行代谢产物的分析,用主成份分析法(PCA)和偏最小二乘法-判别分析(PLS-DA)进行数据处理,获得样品分类信息和差异变量。检索Metlin数据库得到差异代谢产物。根据差异分析结果,选取相关药物对肾脏急性缺血再灌注损伤进行干预,检测生理、生化指标等评价药物的有效性,并探索该药物作用机制。
结果:代谢组学能够在2小时-72小时各时间点区分对照组和缺血再灌注损伤组,代谢物谱能够早于血清肌酐、尿素氮的变化而发现肾脏损伤;差异代谢产物主要有卡尼汀及其衍生物、磷脂酰胆碱分解代谢产物两类,卡尼汀及短链脂酰卡尼汀在缺血再灌注损伤模型血清中含量降低,而后一类物质的血清浓度则有不同程度的升高。选取左旋卡尼汀作为干预急性肾损伤的药物进行研究,初步证实左旋卡尼汀预处理和手术后早期给药可减轻肾脏急性缺血再灌注损伤,可显著改善组织学评分、肾脏功能及组织细胞凋亡情况,其作用机制可能与该药物影响线粒体膜通透性有关。
Objective:To evalute the feasibility of metabolomic technology for developing a rapid and early screen for acute kidney injury,to explore the pathogenessis of AKI and search for new biomarkers and therapy target.Methods: The model of IRI involved bilateral renal artery occlusion for 45 min in male SD rats. Blood samples were taken before the operation or on different time point after reperfusion.24-hour urine samples were colleted on Day 1、2、3 and 4 HPLC-MS-based metabonomic analysis was used to investigate serum and urinary metabolites of the rats.Data were proceeded and subjected to principle component analysis(PCA) and Partial Least Squares-Discriminanl analysis(PLS-DA),then yielded score plots and loading plots,which gave the information about classify and differential metabolites.These differential metabolites were identified by the Metlin database.As the levels of carnitine and its derivatives were decreased in I/R injurt rats according to the primary results,we investigated whether L-carnitine could protect rat kidney from ischemia/reperfusion injury and the mechanism were explored.Results: Changes in the pattern of endogenous metabolites as a result of ischemia/reperfusion injury of rat kidneys were readily detected as early as 2 hours after reperfusion,when was earlier than the increase of BUN and serum creatinine,which were upregulated at 4 hours after reperfusion.The most two kinds of differential metabolites were phosphatidylcholines and carnitines,the former were upregulated and the latter were downregulated.This may indicated that carnitine wre more consumpted in ischemia reperfusion injury.We investigated whether L-camitine could protect rat kidney from ischemia/reperfusion injury.We found that preventive or delayed(just after reperfusion) administration of L-carnitine could abrogate the injury induced by ischemia/reperfusion in rat kidneys,which may be associated with the downregulation of mitochondria membrane permeability by L-carnitine.
结果:代谢组学能够在2小时-72小时各时间点区分对照组和缺血再灌注损伤组,代谢物谱能够早于血清肌酐、尿素氮的变化而发现肾脏损伤;差异代谢产物主要有卡尼汀及其衍生物、磷脂酰胆碱分解代谢产物两类,卡尼汀及短链脂酰卡尼汀在缺血再灌注损伤模型血清中含量降低,而后一类物质的血清浓度则有不同程度的升高。选取左旋卡尼汀作为干预急性肾损伤的药物进行研究,初步证实左旋卡尼汀预处理和手术后早期给药可减轻肾脏急性缺血再灌注损伤,可显著改善组织学评分、肾脏功能及组织细胞凋亡情况,其作用机制可能与该药物影响线粒体膜通透性有关。
Objective:To evalute the feasibility of metabolomic technology for developing a rapid and early screen for acute kidney injury,to explore the pathogenessis of AKI and search for new biomarkers and therapy target.Methods: The model of IRI involved bilateral renal artery occlusion for 45 min in male SD rats. Blood samples were taken before the operation or on different time point after reperfusion.24-hour urine samples were colleted on Day 1、2、3 and 4 HPLC-MS-based metabonomic analysis was used to investigate serum and urinary metabolites of the rats.Data were proceeded and subjected to principle component analysis(PCA) and Partial Least Squares-Discriminanl analysis(PLS-DA),then yielded score plots and loading plots,which gave the information about classify and differential metabolites.These differential metabolites were identified by the Metlin database.As the levels of carnitine and its derivatives were decreased in I/R injurt rats according to the primary results,we investigated whether L-carnitine could protect rat kidney from ischemia/reperfusion injury and the mechanism were explored.Results: Changes in the pattern of endogenous metabolites as a result of ischemia/reperfusion injury of rat kidneys were readily detected as early as 2 hours after reperfusion,when was earlier than the increase of BUN and serum creatinine,which were upregulated at 4 hours after reperfusion.The most two kinds of differential metabolites were phosphatidylcholines and carnitines,the former were upregulated and the latter were downregulated.This may indicated that carnitine wre more consumpted in ischemia reperfusion injury.We investigated whether L-camitine could protect rat kidney from ischemia/reperfusion injury.We found that preventive or delayed(just after reperfusion) administration of L-carnitine could abrogate the injury induced by ischemia/reperfusion in rat kidneys,which may be associated with the downregulation of mitochondria membrane permeability by L-carnitine.
引文
1.Nash K,Hafeez A,Hou S.Hospital-acquired renal insufficiency.Am J Kid ney Dis.2002,39:930-936.
2.Liano F,Pascual J,and the Madrid Acute Renal Failure Study Group.Epidemiology of acute renal failure:A prospective,multicenter,community-based study.Kidney Int.1996,50:811-818.
3.Lameire N,Van Biesen W,Vanholder R.Acute renal failure.Lancet.2005,365:417-30.
4.Kitano H.Systems biology:a brief overview.Science,2002,295(5560):1662-1664.
5.Gelpi E.Contributions of liquid chromatography-mass spectrometry to "highlights" of biomedical research.J Chromatogr A,2003,1000(1-2):567-581.
6.Bellomo R,Ronco C,Kellum JA,et al.Acute renal failure-definition,outcome measures,animal models,fluid therapy and information technology needs:the Second International Consensus Conference of the Acute Dialysis Quality Initiative(ADQI) Group[J].Crit Care.2004,8(4):R204-212.
7.Ichimura T,Bonventre JV,Bailly V,et al.Kidney injury moleeule-1(KIM-1),a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain,is up-regulated in renal cells after injury.J Biol Chem,1998,273(7):4135-4142.
8.Mishra J,Ma Q,Prada A,Mitsnefes M,Zahedi K,Yang J,Barasch J,Rinaldo Bellomo,Claudio Ronco,John A Kellum,Ravindra L Mehta,Paul Palevsky and the ADQI workgroup.Acute renal failure-definition,outcome measures,animal models,fluid therapy and information technology needs:the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.Critical Care.2004,8(4):R204-R212
9.Muramatsu Y,Tsujie M,Kohda Y,et al.Early detection of cysteine rich protein 61(CYR61,CCN1).in urine following renal ischemic reperfusion injury.Kidney Int 2002;62:1601-1610.
10.Hood L.Systems biology:integrating technology,biology,and computation Mech Ageing Dev,2003,124(1):9-16.
11.Liu ET.Systems biology,integrative biology,predictive biology.Cell,2005,121(4):505-506
12.Joyce AR,Palsson BO1The model organism as a system:integrating 'omics'data sets[J]Nat RevMol CellBiol,2006,7(3):198-210
13.Nicholson JK,Wilson ID1Understanding' global' systems biology:metabonomics and the continuum ofmetabolism[J]Nat RevDrugDiscov,2003,2(8):668-676
14.FernieAR,Trethewey RN,KrotzkyAJ,et allMetabolite p rofiling:from diagnostics to systems biology[J]Nat RevMol CellBiol,2004,5(9):763-769
15.WeckwerthW,Morgenthal K1Metabolomics:from pattern recognition to biological interp retation[J]Drug Discov Today,2005,10(22):1551-1558
16.Tweeddale H,Notley-McRobb L,Ferenci T1Effect of slow growth on Kee Bang.Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney.FASEB J.2003 Sep;17(12):1754-5.
61.Plotnikov EY,Kazachenko AV,Vyssokikh MY,Vasileva AK,Tcvirkun DV,Isaev NK,Kirpatovsky Ⅳ,Zorov DB.The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney.Kidney Int.2007Dec;72(12):1493-502.
62.Gorur S,Bagdatoglu OT,Polat G.Protective effect of L-carnitine on renal ischaemia-reperfusion injury in the rat.Cell Biochem Funct.2005May-Jun;23(3):151-5.
63.Usta U,Inan M,Erbas H,Aydogdu N,Oz Puyan F,Altaner S.Tissue damage in rat ovaries subjected to torsion and detorsion:effects of L:-carnitine and N-acetyl cysteine.Pediatr Surg Int.2008 May;24(5):567-73.
64.Guido Kroemer,Lorenzo Galluzzi,Catherine Brenner.Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev 87:99-163,2007.
65.Dokmeci D,Inan M,Basaran UN,Yalcin O,Aydogdu N,Turan FN,Uz YH.Protective effect of L-carnitine on testicular ischaemia-reperfusion injury in rats.Cell Biochem Funct.2007 Nov-Dec;25(6):611-8.
66.L-carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes:role of inhibition of ceramide generation.Andrieu-Abadie N,Jaffrezou JP,Hatem S,Laurent G,Levade T,Mercadier JJ.FASEB J.1999 Sep;13(12):1501-10.
67.Wang C,Sadovova N,Ali HK,Duhart HM,Fu X,Zou X,Patterson TA,Binienda ZK,Virmani A,Paule MG,Slikker W Jr,Ali SF.L-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture.Neuroscience.2007 Jan 5;144(1):46-55.
68.Kroemer G,Dallaporta B,Resche-Rigon M.The mitochondrial death/life regulator in apoptosis and necrosis.Annu Rev Physiol 60:619-642,1998.
69.Mitchell P,Moyle J.Evidence discriminating between the chemical and the chemiosmotic mechanisms of electron transport phosphorylation.Nature 208:1205-1206,1965.
70.Guido Kroemer,Lorenzo Galluzzi,Catherine Brenner.Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev 87:99-163,2007.
71.Marchetti P,Castedo M,Susin SA,Zamzami N,Hirsch T,Macho A,Haeffner A,Hirsch F,Geuskens M,Kroemer G.Mitochondrial permeability transition is a central coordinating event of apoptosis.J Exp Med 184:1155-1160,1996.
72.Zamzami N,Larochette N,Kroemer G.Mitochondrial permeability transition in apoptosis and necrosis.Cell Death Differ 12 Suppl 2:1478-1480,2005.
73.Csordas G,Madesh M,Antonsson B,Hajnoczky G.tcBid promotes Ca signal propagation to the mitochondria:control of Ca permeation through the outer mitochondrial membrane.EMBO J 21:2198-2206,2002.
74.Rapizzi E,Pinton P,Szabadkai G,Wieckowski MR,Vandecasteele G,Baird G,Tuft RA,Fogarty KE,Rizzuto R.Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2_Γ microdomains to mitochondria.J Cell Biol 159:613-624,2002.
75.Rizzuto R,Pozzan T.Microdomains of intracellular Ca:molecular determinantsand functional consequences. Physiol Rev 86: 369-408,2006.
76. Shimizu CM , Ko W C, Wu JS. Mediating of caspase-independent apoptosis by cadmium through the mitochondria-ROS pathway in MRC-5 fibroblasts. Cell Biochem. 2004, 91(2): 384-397.
1. Farley SJ. Acute kidney injury / acute renal failure: standardizing nomenclature, dedinitions and staging [J]. Nat Clin Pract Nephrol. 2007, 3 (8) : 405.
2. Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience [J].. Kidney Int, 2004, 66 (4) : 1613 -1621
3. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group [J]. Crit Care. 2004 ,8(4): R204-212.
4. Molitoris BA, Levin A, Warnock DG, et al. Improving outcomes of acute kidney injury: report of an initiative [J]. Nat Clin Pract Nephrol. 2007,3(8): 439-442.
5. Chertow GM, Burdick E, Honour M, et al. Acute Kidney Injury, Mortality, Length of Stay, and Costs in Hospitalized Patients [J]. J Am Soc Nephrol. 2005, 16 (7):3365-3370.
6. 王海燕．急性肾损伤临床研究的思考与建议[J]．2006, 22 (11): 649-651.
7. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials [J]. Am J Kidney Dis. 2007 ,49(1): 56-68.
1.Brdiczka DG,Zorov DB,Sheu SS.Mitochondrial contact sites:their role in energy metabolism and apoptosis[J].Biochim Biophvs Acta.2006Feb;1762(2):148-63.
2.Bereiter-Hahn J,Voth M.Dynamics of mitochondria in living cells:shape changes,di-slocations,fusion,and fission of mitochondria[J].Microse Res Tech,1994,27:198.
3.Nakada K,Inoue K,Ono T,et al.Inter-mitochondrial complementation:Mitochondria specific system preventing mice from expression of disease phenotypes by mutantmtDNA [J].Nat Med,2001,7:934.
4.Frey TG,Mannella CA.The internal structure of mitochondria[J].Trends Biochem Sci,2000,25:319
5.Scorrano L,Ashiya M,Buttle K,et al.A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis[J].Dev Cell,2002,2:55.
6.Olichon A et al.Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity,leading to cytochrome c release and apoptosis[J].J Biol Chem,2003,278:7743.
7.Boekema EJ,Bram HP.Supr7amolecular structure of the mitochondrial oxidative phosphorylation system[J].J Cell Chem.2007,282(1):1-4.
8.Lenaz G,Baracca A,Fato R,Genova ML,Solaini G.New insights into structure and function of mitochondria and their role in aging and disease.Antioxid Redox Signal[J].2006 Mar-Apr;8(3-4):417-37.
9.Ackerman SH,Tzagoloff A.Function,structure,and biogenesis of mitochondrial ATP synthase[J].Prog Nucleic Acid Res Mol Biol.2005;80:95-133
10.Walker JE,Dickson VK.The peripheral stalk of the mitochondrial ATP synthase.Biochim Biophys Acta[J].2006 May-Jun;1757(5-6):286-296.
11.Kovacic P,Pozos RS,Somanathan R,Shangari N,O'Brien PJ.Mechanism of mitochondrial uncouplers,inhibitors,and toxins:focus on electron transfer,free radicals,and structure-activity relationships[J].Curr Med Chem.2005,12(22):2601-23.dysfunction? [J]J.Ann NY Acad Sci, 2004, 1011: 168-176.
71. STADLER K, JENEI V, vonBOLCSHAZY G. et al. Role of free radicals and reactive nitrogen species in the late complications of diabetes mellitus in rats[J]. Orv Hetil, 2004, 145(21):1135-1140.
72. ROSEN P, NAWROTHP P, KING G, et al. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society[J]. Diabetes Metab Res Rev, 2001, 17(3):189-212.
73. SHA W S, WANG X, REDD H, et al. High glucose augments the angiotensin Ⅱ-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway[J]. J Biol Chem, 2003, 278(33): 30634-30641.
74. HIGASHI Y, YOSHIZUMI M. Endothelial function[J]. Nippon Rinsho, 2003,61(7):1138-1144.
2.Liano F,Pascual J,and the Madrid Acute Renal Failure Study Group.Epidemiology of acute renal failure:A prospective,multicenter,community-based study.Kidney Int.1996,50:811-818.
3.Lameire N,Van Biesen W,Vanholder R.Acute renal failure.Lancet.2005,365:417-30.
4.Kitano H.Systems biology:a brief overview.Science,2002,295(5560):1662-1664.
5.Gelpi E.Contributions of liquid chromatography-mass spectrometry to "highlights" of biomedical research.J Chromatogr A,2003,1000(1-2):567-581.
6.Bellomo R,Ronco C,Kellum JA,et al.Acute renal failure-definition,outcome measures,animal models,fluid therapy and information technology needs:the Second International Consensus Conference of the Acute Dialysis Quality Initiative(ADQI) Group[J].Crit Care.2004,8(4):R204-212.
7.Ichimura T,Bonventre JV,Bailly V,et al.Kidney injury moleeule-1(KIM-1),a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain,is up-regulated in renal cells after injury.J Biol Chem,1998,273(7):4135-4142.
8.Mishra J,Ma Q,Prada A,Mitsnefes M,Zahedi K,Yang J,Barasch J,Rinaldo Bellomo,Claudio Ronco,John A Kellum,Ravindra L Mehta,Paul Palevsky and the ADQI workgroup.Acute renal failure-definition,outcome measures,animal models,fluid therapy and information technology needs:the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.Critical Care.2004,8(4):R204-R212
9.Muramatsu Y,Tsujie M,Kohda Y,et al.Early detection of cysteine rich protein 61(CYR61,CCN1).in urine following renal ischemic reperfusion injury.Kidney Int 2002;62:1601-1610.
10.Hood L.Systems biology:integrating technology,biology,and computation Mech Ageing Dev,2003,124(1):9-16.
11.Liu ET.Systems biology,integrative biology,predictive biology.Cell,2005,121(4):505-506
12.Joyce AR,Palsson BO1The model organism as a system:integrating 'omics'data sets[J]Nat RevMol CellBiol,2006,7(3):198-210
13.Nicholson JK,Wilson ID1Understanding' global' systems biology:metabonomics and the continuum ofmetabolism[J]Nat RevDrugDiscov,2003,2(8):668-676
14.FernieAR,Trethewey RN,KrotzkyAJ,et allMetabolite p rofiling:from diagnostics to systems biology[J]Nat RevMol CellBiol,2004,5(9):763-769
15.WeckwerthW,Morgenthal K1Metabolomics:from pattern recognition to biological interp retation[J]Drug Discov Today,2005,10(22):1551-1558
16.Tweeddale H,Notley-McRobb L,Ferenci T1Effect of slow growth on Kee Bang.Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney.FASEB J.2003 Sep;17(12):1754-5.
61.Plotnikov EY,Kazachenko AV,Vyssokikh MY,Vasileva AK,Tcvirkun DV,Isaev NK,Kirpatovsky Ⅳ,Zorov DB.The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney.Kidney Int.2007Dec;72(12):1493-502.
62.Gorur S,Bagdatoglu OT,Polat G.Protective effect of L-carnitine on renal ischaemia-reperfusion injury in the rat.Cell Biochem Funct.2005May-Jun;23(3):151-5.
63.Usta U,Inan M,Erbas H,Aydogdu N,Oz Puyan F,Altaner S.Tissue damage in rat ovaries subjected to torsion and detorsion:effects of L:-carnitine and N-acetyl cysteine.Pediatr Surg Int.2008 May;24(5):567-73.
64.Guido Kroemer,Lorenzo Galluzzi,Catherine Brenner.Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev 87:99-163,2007.
65.Dokmeci D,Inan M,Basaran UN,Yalcin O,Aydogdu N,Turan FN,Uz YH.Protective effect of L-carnitine on testicular ischaemia-reperfusion injury in rats.Cell Biochem Funct.2007 Nov-Dec;25(6):611-8.
66.L-carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes:role of inhibition of ceramide generation.Andrieu-Abadie N,Jaffrezou JP,Hatem S,Laurent G,Levade T,Mercadier JJ.FASEB J.1999 Sep;13(12):1501-10.
67.Wang C,Sadovova N,Ali HK,Duhart HM,Fu X,Zou X,Patterson TA,Binienda ZK,Virmani A,Paule MG,Slikker W Jr,Ali SF.L-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture.Neuroscience.2007 Jan 5;144(1):46-55.
68.Kroemer G,Dallaporta B,Resche-Rigon M.The mitochondrial death/life regulator in apoptosis and necrosis.Annu Rev Physiol 60:619-642,1998.
69.Mitchell P,Moyle J.Evidence discriminating between the chemical and the chemiosmotic mechanisms of electron transport phosphorylation.Nature 208:1205-1206,1965.
70.Guido Kroemer,Lorenzo Galluzzi,Catherine Brenner.Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev 87:99-163,2007.
71.Marchetti P,Castedo M,Susin SA,Zamzami N,Hirsch T,Macho A,Haeffner A,Hirsch F,Geuskens M,Kroemer G.Mitochondrial permeability transition is a central coordinating event of apoptosis.J Exp Med 184:1155-1160,1996.
72.Zamzami N,Larochette N,Kroemer G.Mitochondrial permeability transition in apoptosis and necrosis.Cell Death Differ 12 Suppl 2:1478-1480,2005.
73.Csordas G,Madesh M,Antonsson B,Hajnoczky G.tcBid promotes Ca signal propagation to the mitochondria:control of Ca permeation through the outer mitochondrial membrane.EMBO J 21:2198-2206,2002.
74.Rapizzi E,Pinton P,Szabadkai G,Wieckowski MR,Vandecasteele G,Baird G,Tuft RA,Fogarty KE,Rizzuto R.Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2_Γ microdomains to mitochondria.J Cell Biol 159:613-624,2002.
75.Rizzuto R,Pozzan T.Microdomains of intracellular Ca:molecular determinantsand functional consequences. Physiol Rev 86: 369-408,2006.
76. Shimizu CM , Ko W C, Wu JS. Mediating of caspase-independent apoptosis by cadmium through the mitochondria-ROS pathway in MRC-5 fibroblasts. Cell Biochem. 2004, 91(2): 384-397.
1. Farley SJ. Acute kidney injury / acute renal failure: standardizing nomenclature, dedinitions and staging [J]. Nat Clin Pract Nephrol. 2007, 3 (8) : 405.
2. Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience [J].. Kidney Int, 2004, 66 (4) : 1613 -1621
3. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group [J]. Crit Care. 2004 ,8(4): R204-212.
4. Molitoris BA, Levin A, Warnock DG, et al. Improving outcomes of acute kidney injury: report of an initiative [J]. Nat Clin Pract Nephrol. 2007,3(8): 439-442.
5. Chertow GM, Burdick E, Honour M, et al. Acute Kidney Injury, Mortality, Length of Stay, and Costs in Hospitalized Patients [J]. J Am Soc Nephrol. 2005, 16 (7):3365-3370.
6. 王海燕．急性肾损伤临床研究的思考与建议[J]．2006, 22 (11): 649-651.
7. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials [J]. Am J Kidney Dis. 2007 ,49(1): 56-68.
1.Brdiczka DG,Zorov DB,Sheu SS.Mitochondrial contact sites:their role in energy metabolism and apoptosis[J].Biochim Biophvs Acta.2006Feb;1762(2):148-63.
2.Bereiter-Hahn J,Voth M.Dynamics of mitochondria in living cells:shape changes,di-slocations,fusion,and fission of mitochondria[J].Microse Res Tech,1994,27:198.
3.Nakada K,Inoue K,Ono T,et al.Inter-mitochondrial complementation:Mitochondria specific system preventing mice from expression of disease phenotypes by mutantmtDNA [J].Nat Med,2001,7:934.
4.Frey TG,Mannella CA.The internal structure of mitochondria[J].Trends Biochem Sci,2000,25:319
5.Scorrano L,Ashiya M,Buttle K,et al.A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis[J].Dev Cell,2002,2:55.
6.Olichon A et al.Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity,leading to cytochrome c release and apoptosis[J].J Biol Chem,2003,278:7743.
7.Boekema EJ,Bram HP.Supr7amolecular structure of the mitochondrial oxidative phosphorylation system[J].J Cell Chem.2007,282(1):1-4.
8.Lenaz G,Baracca A,Fato R,Genova ML,Solaini G.New insights into structure and function of mitochondria and their role in aging and disease.Antioxid Redox Signal[J].2006 Mar-Apr;8(3-4):417-37.
9.Ackerman SH,Tzagoloff A.Function,structure,and biogenesis of mitochondrial ATP synthase[J].Prog Nucleic Acid Res Mol Biol.2005;80:95-133
10.Walker JE,Dickson VK.The peripheral stalk of the mitochondrial ATP synthase.Biochim Biophys Acta[J].2006 May-Jun;1757(5-6):286-296.
11.Kovacic P,Pozos RS,Somanathan R,Shangari N,O'Brien PJ.Mechanism of mitochondrial uncouplers,inhibitors,and toxins:focus on electron transfer,free radicals,and structure-activity relationships[J].Curr Med Chem.2005,12(22):2601-23.dysfunction? [J]J.Ann NY Acad Sci, 2004, 1011: 168-176.
71. STADLER K, JENEI V, vonBOLCSHAZY G. et al. Role of free radicals and reactive nitrogen species in the late complications of diabetes mellitus in rats[J]. Orv Hetil, 2004, 145(21):1135-1140.
72. ROSEN P, NAWROTHP P, KING G, et al. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society[J]. Diabetes Metab Res Rev, 2001, 17(3):189-212.
73. SHA W S, WANG X, REDD H, et al. High glucose augments the angiotensin Ⅱ-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway[J]. J Biol Chem, 2003, 278(33): 30634-30641.
74. HIGASHI Y, YOSHIZUMI M. Endothelial function[J]. Nippon Rinsho, 2003,61(7):1138-1144.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |