去铁胺对缺血性急性肾衰竭大鼠的保护作用
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摘要
目的:探讨去铁胺(DFO)对缺血性急性肾衰竭(iARF)大鼠的保护作用及其作用机制,为DFO更好地应用于临床iARF提供实验性理论依据。
方法:
1、iARF大鼠模型的制备用钳夹大鼠双侧肾蒂45min的方法制成iARF动物模型。
2、雄性Wistar大鼠,随机分成3组:假手术组、手术组、DFO+手术组,每组各12只。手术组:用无损伤动脉夹钳夹大鼠双侧肾蒂45min,然后松开动脉夹,实行再灌注。肉眼见肾脏由暗红变为鲜红,表明再灌注成功(实验过程中动物体温维持在37℃左右),关闭腹腔后继续饲养,缺血前24小时给予等体积生理盐水腹腔注射。假手术组同法打开腹腔并找到肾蒂,但不夹闭肾蒂,后关闭腹腔,打开腹腔前24h给予等体积生理盐水腹腔注射。DFO+手术组:缺血前24小时给予DFO (200mg/kg)腹腔注射,其余处理同手术组。于缺血再灌注24h后检测血尿素氮(BUN)、肌酐(Scr)、超氧化物岐化酶(SOD)、丙二醛(MDA)的含量以及进行肾组织光镜形态学观察和采用免疫组织化学法测定低氧诱导因子-1α(HIF-1α)及血红素加氧酶-1(HO-1)蛋白的表达水平。
结果:
1、肾组织形态学改变大体:假手术组为正常肾组织;手术组肾脏外形肿大,剖面见皮质肿胀,色苍白,髓质呈暗红色;DFO干预组肾脏外观与正常接近。HE染色:假手术组肾小球、肾小管结构大致正常;手术组肾小管上皮细胞均有不同程度的坏死,间质水肿,大量炎细胞浸润,血管渗透性增加,红细胞溢出;DFO干预组病理改变明显减轻,仅肾小管上皮轻度肿胀。
2、手术组大鼠于缺血再灌注后24h的BUN、Scr值显著高于假手术组(P﹤0.01),但DFO+手术组与手术组比,BUN、Scr值却明显降低(P<0.01)。
3、手术组大鼠肾组织MDA含量显著高于假手术组(P﹤0.01),但DFO+手术组MDA含量与手术组比却明显降低(P<0.01)。手术组大鼠肾组织SOD活力显著低于假手术组(P﹤0. 01),但DFO+手术组SOD活力明显高于手术组(P﹤0.01)。
4、HIF-1α阳性表达为肾小管上皮细胞胞核及部分胞浆内出现棕黄色颗粒,HO-1阳性表达为细胞胞浆出现棕黄色颗粒。假手术组未见阳性细胞,手术组、DFO+手术组显示HIF-1α、HO-1有不同程度的阳性表达,手术组大鼠肾小管上皮细胞HIF-1α、HO-1的阳性表达呈弱阳性,但DFO+手术组HIF-1α、HO-1的表达呈强阳性,各组均未发现肾小球及间质细胞染色阳性。图像分析表明:手术组、DFO+手术组大鼠肾小管上皮细胞HIF-1α、HO-1灰度值水平明显低于假手术组(P﹤0.01),DFO+手术组与手术组比灰度值明显降低(P均﹤0.01)。
结论:
1、DFO预处理能显著减轻iARF大鼠肾功能损害程度,在病理上明显减轻肾小管损伤程度。
2、DFO预处理可通过自由基清除和诱导HIF-1α及下游基因HO-1过表达从而对iARF大鼠发挥保护作用。
Objective: To explore the protective effects and mechanism of deferoxamine (DFO) in ischemic acute renal failure(iARF) rats and provide experimental theory basis for the DFO’s clinical application of iARF .
Methods:
1、Establishment of iARF rat model. Bilateral clipping of renal arteries for 45min.
2、Thirty-six male Wistar rats were randomly and averagely divided into three groups : sham、surgery and DFO+ surgery groups. In surgery group,ischemic acute renal failure model was established by bilateral clipping of renal arteries for 45min and reperfusion for 24 hours.Observe the color of renal when it from dark red into bright red that means reperfusion success(the temperature of experimental animals maintained at around 37℃in this process), keeping after close abdominal cavity, and injected the rat with the same size saline throuh intraperitoneal 24 hours before the modle was established. In group sham, find renal arteries but not clip,,the other protocals were same as group model. In group DFO+ surgery,DFO was intraperitoneal injected (200mg/kg) to rats 24h before 45 min renal ischemia,the other protocals were same as group model. Activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA), blood urea nitrogen (BUN),serum creatinine (Scr) were examined.Structure of the kidney was observed under optical microscope.The expression of HIF-1α、HO-1 was detected by immunohistochemistry .
Results:
1、Morphological changes of renal tissue general: In Sham group renal tissue was normal; in surgery group, the appearance of kidney was saw enlargement section ,cortical swelling,pale color, medulla was dark red; the appearance of kidney was almost normal in DFO + surgery group. Histopathological changes(HE): Normal morphology was observed by optical microscopy in group sham. Red blood cells in glomerulus were seen and swelling cells of renal tubules appeared without inflammatory cell infiltrated and necrosis foci in group surgery. Only red blood cells in glomerulus were seen in group DFO + surgery group.
2、Twenty- four hour after reperfusion,the levels of BUN and Scr were significantly higher in the surgery group than in the sham group(P﹤0.01),but the levels of BUN and Scr were marked downturn in the DFO + surgey group than in the surgery
3、Twenty- four hour after reperfusion,the content of MDA were significantly higher in the surgery group than in the sham group,but the content of MDA were marked downturn in the DFO + surgey group than in the surgery(P﹤0.01).SOD just the opposite(P<0.01).
4、Immunohistochemical study showed that the levels of HIF-1αwas positive expression in the nuclear and in the plasma ,and the levels of HO-1 was positive expression in the plasma and surface of cava of renal tubule cells. There is no positive staining in group sham.Tubule cells expressed low levels of HIF-1α、HO-1 protein in group surgery,the highest levels of HIF-1α、HO-1 were detected in group DFO+ surgery.Glomerulus and interstitial cells were not staind. Image analysis showed that difference between the two groups was significant (P<0.01).
Conclusion:
1、DFO pretreatment can significantly reduce the injury of renal function and the pathological extent of renal tubular injury in iARF rats.
2、DFO pretreatment can protect iARF rats by clearing the free radical and inducing the over-expression of hypoxia factor-1αand hemeoxygenase-1.
方法:
1、iARF大鼠模型的制备用钳夹大鼠双侧肾蒂45min的方法制成iARF动物模型。
2、雄性Wistar大鼠,随机分成3组:假手术组、手术组、DFO+手术组,每组各12只。手术组:用无损伤动脉夹钳夹大鼠双侧肾蒂45min,然后松开动脉夹,实行再灌注。肉眼见肾脏由暗红变为鲜红,表明再灌注成功(实验过程中动物体温维持在37℃左右),关闭腹腔后继续饲养,缺血前24小时给予等体积生理盐水腹腔注射。假手术组同法打开腹腔并找到肾蒂,但不夹闭肾蒂,后关闭腹腔,打开腹腔前24h给予等体积生理盐水腹腔注射。DFO+手术组:缺血前24小时给予DFO (200mg/kg)腹腔注射,其余处理同手术组。于缺血再灌注24h后检测血尿素氮(BUN)、肌酐(Scr)、超氧化物岐化酶(SOD)、丙二醛(MDA)的含量以及进行肾组织光镜形态学观察和采用免疫组织化学法测定低氧诱导因子-1α(HIF-1α)及血红素加氧酶-1(HO-1)蛋白的表达水平。
结果:
1、肾组织形态学改变大体:假手术组为正常肾组织;手术组肾脏外形肿大,剖面见皮质肿胀,色苍白,髓质呈暗红色;DFO干预组肾脏外观与正常接近。HE染色:假手术组肾小球、肾小管结构大致正常;手术组肾小管上皮细胞均有不同程度的坏死,间质水肿,大量炎细胞浸润,血管渗透性增加,红细胞溢出;DFO干预组病理改变明显减轻,仅肾小管上皮轻度肿胀。
2、手术组大鼠于缺血再灌注后24h的BUN、Scr值显著高于假手术组(P﹤0.01),但DFO+手术组与手术组比,BUN、Scr值却明显降低(P<0.01)。
3、手术组大鼠肾组织MDA含量显著高于假手术组(P﹤0.01),但DFO+手术组MDA含量与手术组比却明显降低(P<0.01)。手术组大鼠肾组织SOD活力显著低于假手术组(P﹤0. 01),但DFO+手术组SOD活力明显高于手术组(P﹤0.01)。
4、HIF-1α阳性表达为肾小管上皮细胞胞核及部分胞浆内出现棕黄色颗粒,HO-1阳性表达为细胞胞浆出现棕黄色颗粒。假手术组未见阳性细胞,手术组、DFO+手术组显示HIF-1α、HO-1有不同程度的阳性表达,手术组大鼠肾小管上皮细胞HIF-1α、HO-1的阳性表达呈弱阳性,但DFO+手术组HIF-1α、HO-1的表达呈强阳性,各组均未发现肾小球及间质细胞染色阳性。图像分析表明:手术组、DFO+手术组大鼠肾小管上皮细胞HIF-1α、HO-1灰度值水平明显低于假手术组(P﹤0.01),DFO+手术组与手术组比灰度值明显降低(P均﹤0.01)。
结论:
1、DFO预处理能显著减轻iARF大鼠肾功能损害程度,在病理上明显减轻肾小管损伤程度。
2、DFO预处理可通过自由基清除和诱导HIF-1α及下游基因HO-1过表达从而对iARF大鼠发挥保护作用。
Objective: To explore the protective effects and mechanism of deferoxamine (DFO) in ischemic acute renal failure(iARF) rats and provide experimental theory basis for the DFO’s clinical application of iARF .
Methods:
1、Establishment of iARF rat model. Bilateral clipping of renal arteries for 45min.
2、Thirty-six male Wistar rats were randomly and averagely divided into three groups : sham、surgery and DFO+ surgery groups. In surgery group,ischemic acute renal failure model was established by bilateral clipping of renal arteries for 45min and reperfusion for 24 hours.Observe the color of renal when it from dark red into bright red that means reperfusion success(the temperature of experimental animals maintained at around 37℃in this process), keeping after close abdominal cavity, and injected the rat with the same size saline throuh intraperitoneal 24 hours before the modle was established. In group sham, find renal arteries but not clip,,the other protocals were same as group model. In group DFO+ surgery,DFO was intraperitoneal injected (200mg/kg) to rats 24h before 45 min renal ischemia,the other protocals were same as group model. Activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA), blood urea nitrogen (BUN),serum creatinine (Scr) were examined.Structure of the kidney was observed under optical microscope.The expression of HIF-1α、HO-1 was detected by immunohistochemistry .
Results:
1、Morphological changes of renal tissue general: In Sham group renal tissue was normal; in surgery group, the appearance of kidney was saw enlargement section ,cortical swelling,pale color, medulla was dark red; the appearance of kidney was almost normal in DFO + surgery group. Histopathological changes(HE): Normal morphology was observed by optical microscopy in group sham. Red blood cells in glomerulus were seen and swelling cells of renal tubules appeared without inflammatory cell infiltrated and necrosis foci in group surgery. Only red blood cells in glomerulus were seen in group DFO + surgery group.
2、Twenty- four hour after reperfusion,the levels of BUN and Scr were significantly higher in the surgery group than in the sham group(P﹤0.01),but the levels of BUN and Scr were marked downturn in the DFO + surgey group than in the surgery
3、Twenty- four hour after reperfusion,the content of MDA were significantly higher in the surgery group than in the sham group,but the content of MDA were marked downturn in the DFO + surgey group than in the surgery(P﹤0.01).SOD just the opposite(P<0.01).
4、Immunohistochemical study showed that the levels of HIF-1αwas positive expression in the nuclear and in the plasma ,and the levels of HO-1 was positive expression in the plasma and surface of cava of renal tubule cells. There is no positive staining in group sham.Tubule cells expressed low levels of HIF-1α、HO-1 protein in group surgery,the highest levels of HIF-1α、HO-1 were detected in group DFO+ surgery.Glomerulus and interstitial cells were not staind. Image analysis showed that difference between the two groups was significant (P<0.01).
Conclusion:
1、DFO pretreatment can significantly reduce the injury of renal function and the pathological extent of renal tubular injury in iARF rats.
2、DFO pretreatment can protect iARF rats by clearing the free radical and inducing the over-expression of hypoxia factor-1αand hemeoxygenase-1.
引文
[1] Vijayan A, Miller SB. Acute renal failure:prevention and nondialytic therapy. Semin Nephrol, 1998,18(5): 523~532.
[2] Deng J, Kohda Y, Chiao H, et al. Interleukin- 10 inhibits ischemicand cisplatin- induced acute renal injury. Kidney Int, 2001,60(6):2118~2128.
[3] Chen YM, Chien CT, Hu-Tsai MI, et al. Pentoxifylline attenuates experimental mesangial proliferative glomerulonephritis. Kidney Int.,1999 Sep;56(3):932~943.
[4] Dobashi K, Ghosh B, Orak JK,et al. Kidney ischemia reperfusion: modulation of antioxidant defenses.Mol Cell Biochem,2000,205(1-2):1~11.
[5]夏安周,邢淑华,张昭辉,等.大鼠肾缺血再灌注程中脂质过氧化损伤的实验研究.徐州医学院学报,2004,24(2):109~111.
[6] Puller MS, Hedlund BE,Sikora JJ,et al. Role of iron in postischemic renal injury in the rat. Kidney Int,1988, 34(4):474~480.
[7] GL Semenza, GL Wang. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.MOL Cell Biol,1992,12(12):5447~5454.
[8] Stroka DM, Burkhardt T, Desbaillets I, et al. HIF-1 is expressed in tissue and displays an regulation under systemic hypoxie. FASEB j, 2001,15(3):2445~2453.
[9] Rosenberger C, Heyman SN, Rosen S, et al. Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia. Kidney Int, 2005,67;531~542.
[10] Matsumoto M, Makino Y, Tanaka T, et al. Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats .J American Society of Nephrology , 2003,14(7):1825~1832.
[11] Katori M, Buelow R, Ke B, et al. Heme oxygenase-1 overexpression protects rat hearts from cold ischemia-reperfusion injury via an antiapoptotic pathway. Transplantation, 2002, 73(2):287~292.
[12] Fondevila C, Shen XD, Tsuchiyashi S, et al. Biliverdin therapy protects rat livers from ischemia and reperfusion injury. Hepatology, 2004, 40(6): 1333~1341.
[13] Nakao A, Kimizuka K, Stolz DB, et al. Protective effect of carbon monoxide inhalation for cold-preserved small intestinal grafts. Surgery, 2003, 134(2):285~292.
[14]黄越芳,庄思齐.去铁胺对新生大鼠缺氧缺血性脑损伤的保护作用.广东医学, 2003,24:696~698.
[15] Yonezawa M, Back SA , Gan X,et al. Cystine deprivation induces oligodendroglial death: rescue by free radical scavengers and by a diffusible glial factor. J Neurochem, 1996 , 67 (2) :566~573.
[16] Jones NM, Bergeron M. Hypoxic preconditioning induces changes in HIF– 1 target genes in neonatal rat brain. J Cereb Blood Flow Metab ,2001 ,21(9) :1105~1114.
[17] Vartiainen N , Keksa-Goldsteine V , Goldsteins G, et al. Aspirin inhibits p44/42 mitogen-activated protein kinase and is protective against hypoxia/reoxygenation neuronal damage. Sroke,2003,34(3):752~757.
[18] Sharp FR, Bergeron M, Bernaudin M. Hypoxia-inducible factor in brain. Adv Exp Med Biol,2001,502 :273~291.
[19] Bergeron M, Gidday JM ,Yu AY, et al. Role of Hypoxia-inducible factor-1 in hypoxia- induced ischemic tolerance in neonatal rat brain. Ann Neurol ,2000,48(3) :285~296.
[20]张力,陈珊琳.腺苷对大鼠缺血性急性肾衰竭的干预作用.实用儿科临床杂志, 2006,21(5):290~291.
[21] Vyacheslav Y. Melnikov SF, Britta SM, et al. Neutrophilindependent mechanisms of Caspase-1 and IL-18-mediated ischemic acute tubular necrosis in mice. J ClinInvest, 2002, 110: 1083~1091.
[22]张萱,韩丽姝,徐晋,等.肾缺血再灌注损伤和丹参的保护作用的实验研究.解剖科学进展,1996,2(3):269~272.
[23] Raff U, Schneider R, Gambaryan S,et al . L-Arginine does not affect renal morphology and cell survival in ischemic acute renal failure in rats. Nephron Physiol, 2005,101(3): 39~50.
[24] Sheridan AM, Bonventre JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens ,2000,9 :427 ~ 434.
[25] Bernhardt WM, Campean V, Kany S, et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol, 2006, 17(7):1970~1978.
[26] Reiter RJ, Poeggeler B, Dun-xian, et al. Antioxidant capacity of melatonin: Anovelactionnotrequiringre-ceptor. NeuroendocrinolLett, 1993,15:103~116.
[27] Marshall KA, Reiter RJ, Poeggeler B,et al. Evaluation of the antioxidant activity of melatonin in vitro. Free Radical Biology&Medicine, 1996,21(3): 307~315.
[28] Srinivas V, Zhang LP, Zhu XH, et al. Characterization of an oxygen/ redox -dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins. Biochem Biophys Res Commun, 1999, 260(2):557~561.
[29] Tanimoto K, Makino Y, Pereira T, et al. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J, 2000, 19(16):4298~4309.
[30] Min JH, Yang H, Ivan M, et al. Structure of an HIF-lalpha -pVHL complex: hydroxyproline recognition in signaling. Science, 2002 ,296(5574):1886~1889.
[31] Lando D, Peet DJ, Whelan DA. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science, 2002 ,295(5556):858~861.
[32] Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA binding activity:implications for models of hypoxia signal transduction. Blood. 1993,82:3610~3615.
[33] Wang GL, Jiang BH, Rue EA, Semenza Gh. Hypoxia-inducible factor 1 is a basic-helix- loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995,92:5510~5514.
[34] Zaman K, Ryu H, Hall D, et al.Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, and erythropoietin. J Neurosci,1999, 19:9821~9830
[35] Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor -1αis mediated by an O2-dependent degradation domain via theubiquitin-proteasome pathway. Proc Natl Acad Sci, USA. 1998:7987~7992.
[36] Kallio PJ, Wilson WJ, O'Brien S, Makino Y. and Poellinger L. Regulation of the hypoxia-inducible transcription factor-1 a by the ubiquitin-proteasome pathway. J Biol Chem, 1999, 274: 6519~6525.
[37] Ivan M.,et al.HIF-1a targeted for VHL-mediated destruction by praline hydroxylation: implications for O2sensing. Science,2001,292:464~468.
[38] Bruick RK, Mcknighy SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001,294:1337~1340.
[39] McNeill LA, Hewitson KS, Gleadle JM, et al.The use of dioxygen by HIF prolyhydroxylase l (PHD1).Bioorg Medical Chem Lett. 2002,12: 1547~1550.
[40] Min JH, Yang HF, Ivan M, et al. Structrue of an HIF-1 a–pVHL complex: Hydroxyproline recognition in signaling. Science. 2002, 296:1886~1889.
[41] Londo D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes&Development. 2002,16:1466~1471.
[42] Hewitson KS, Mcneill LA, Riordan MV, Tian YM, et al. Hypoxia-inducible factor(HIF) asparagines hydroxylase is identical to factor inhibiting HIF(FIH) and is related to the cupin structural family. J Biol Chem. 2002, 277: 26351~26355.
[43] Dames SA, Martinet YM, De Guzman RN, et al. Structural basis for HIF a/CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci. 2002, 99: 5271~5276.
[44] Foresti R, Goatly H, Green CJ, et al. Role of heme oxygenase-1 in hypoxia- reoxygenation: requirement of substrate heme to promote cardioprotection. Am J Physiol Heart Circ Physiol, 2001,281(5): H1976~1984.
[45] Katori M, Anselmo DM, Busuttil RW, et al. A novel strategy against ischemia and reperfusion injury: cytoprotection with heme oxygenase system.Transpl Immunol, 2002,9(2-4):227~233.
[46] Horikawa S, Yoneya R, Nagashima丫et al. Prior induction of heme oxygenase-1 with glutathione depletory ameliorates the renal ischemia and reperfusion injury in the rat. FEBS Lett, 2002, 510(3): 221~224.
[47] Vulapalli SR, Chen Z, Chua BH, et al. Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis. Am J Physiol Heart Circ Physiol, 2002 283(2): H688~694.
[48] Guo X, Shin VY, Cho CH. Modulation of heme oxygenase in tissue injury and its implication in protection against gastrointestinal diseases. Life Sci, 2001, 69(25-26): 3113~3119.
[49] Stefan G, Melina NK, Roland B, et al. Inhibition of ischemia reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt protoporphyrin for the induction of heme oxygenase-1. Transplatation, 2002,74:591~598.
[50] Mahin D, Maines. Spin Trap(N-t-butyl- a -phenylnitrone)-mediated suprainduction of heme oxygenase-1 in kidney ischemia/reperfusion model:Role of the oxygenase in protection against oxidative injury.The J Pharmacology and Experimental 1999; 291(2): 911~920.
[51] Elbirt KK, Whitmarsh AJ, Davis RJ, et al. Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. J Biol Chem, 1998, 273:8922~8931.
[52] Hiroko S, Toru T, Tsutomu S, et al. Protective effect of heme oxygenase induction in ischemic acute renal failure. Crit Care Med, 2000,28:809~817.
[53] Akagi R, Takahashi T, Sassa S. Fundamental role of heme oxygenase in the protection against ischemic acute renal failure. Jpn J Pharmacol, 2002, 88(2): 127~132.
[54] Ishizuka S, Nagashima Y, Numata M, et al. Regulation and immunohistochemical analysis of stress protein heme oxygenase-1 in rat kidney with myoglobinuric acute renal failure. Biochem Biophys Res Commun, 1997,240:93~98.
[55] Nath KA, Balla G,Vercellotti GM, et al. Induction of heme oxygenase is arapid,protective response in rhabdomyolysis in the rat. J Clin Invest, 1992, 90:267~270.
[56]Prass K, Ruscher K, Karsch M, et al. Desferrioxamine induced delayed tolerance against cerebral ischemia in vivo and in vitro. J Cereb Blood Flow Metab,2002, 22 (5) :520~525.
[57]Yang ZZ, Zou AP. Transcriptional regulation of heme oxygenases by HIF-lalpha in renal medullary interstitial cells. Am J Physiol Renal Physiol,2001,281 (5): 900~908.
[58]章斌,陈楠,邢静萍,等.缺血再灌注肾损伤中血红素加氧酶-1的表达及其意义.中华肾脏病杂志,2004,20:214~215.
[1] Florian T, Zhuma H, Kathleen W,et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol, 2005, 289: 31~42.
[2]Makiko M, Yuichi M, Tetsuhiro T,et al. Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats. American Society ofNephrology ,2003,14:1825~1832.
[3]王晗.缺氧诱导因子—1与细胞凋亡.国外医学.生理病理学与临床分册,2005, 25 (1):52~56.
[4]Rosenberger C,Heyman SN,Rosen S,et al .Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia.Kidney lnt,2005,67(2):531~542.
[5]Rosenbergerc,Mandriota S,Jtirgensen S,et a1. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol,2002,13(7):1721~1732.
[6]Matsumoto M,Makino Y,Tanaka T,et a1.Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats.J Am Soc Nephrol,2003,14:1825~1832.
[7]Shimizu H,Takahashi T,Suzuki T,et a1.Protective effect of heme oxygenase induction in ischemic acute renal failure.Crit Care Med, 2000,28:809~817.
[8]平蕾,沈霞,耿德勤等.促红细胞生成素对大鼠局灶性脑缺血CAPSASE—3蛋白的影响.神经疾病与精神卫生,2004,4(5):337~340.
[9]Junk AK, Mammis A, Savitz SI, et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci US A,2002,99 (16): 10659~10664.
[10]Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the H IF system. NatMed, 2003, 9 (6):677~ 684.
[11]ZhangQZ, Zhang ZF, Rao JY, et al. Treatment with siRNA and antisense oligonucleotides targeted to H IF-1αinduced apoptosis in human tongue squamous cell carcinomas. Int J Cancer, 2004,111: 849~ 857.
[12]Hellwig-Burgel T, Stiehl DP, Katschinski DM, et al. VEGF Production by primary human renal proximal tubular cells: requirement of HIF-1, PI32 -kinase and MAPKK-1 signaling. Cell Physiol Biochem,2005,15(1-4):99~108.
[13]Kanellis J,Mudge SJ,Fraser S, et al. Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury . Kidney Int , 2000 ,57 (6) : 2445~2456.
[14]Cozzi A, Levi S, Corsi B, et al. Role of iron and ferritin in TNFalpha-induced apoptosis in HeLa cells. FEBS Lett, 2003, 537(1-3):187~92.
[15] Graca-Souza AV, Arruda MA, de Freitas MS, et al. Neutrophil activation by heme: implications for inflammatory processes. Blood, 2002, 99(11):4160~4165.
[16] Matsumoto M, Makino Y, Tanaka T, et al. Induction of Renoprotective Gene Expression byCobalt Ameliorates Ischemic Injury of the Kidney in Rats .J American Society of Nephrology , 2003,14(7):1825~1832.
[2] Deng J, Kohda Y, Chiao H, et al. Interleukin- 10 inhibits ischemicand cisplatin- induced acute renal injury. Kidney Int, 2001,60(6):2118~2128.
[3] Chen YM, Chien CT, Hu-Tsai MI, et al. Pentoxifylline attenuates experimental mesangial proliferative glomerulonephritis. Kidney Int.,1999 Sep;56(3):932~943.
[4] Dobashi K, Ghosh B, Orak JK,et al. Kidney ischemia reperfusion: modulation of antioxidant defenses.Mol Cell Biochem,2000,205(1-2):1~11.
[5]夏安周,邢淑华,张昭辉,等.大鼠肾缺血再灌注程中脂质过氧化损伤的实验研究.徐州医学院学报,2004,24(2):109~111.
[6] Puller MS, Hedlund BE,Sikora JJ,et al. Role of iron in postischemic renal injury in the rat. Kidney Int,1988, 34(4):474~480.
[7] GL Semenza, GL Wang. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.MOL Cell Biol,1992,12(12):5447~5454.
[8] Stroka DM, Burkhardt T, Desbaillets I, et al. HIF-1 is expressed in tissue and displays an regulation under systemic hypoxie. FASEB j, 2001,15(3):2445~2453.
[9] Rosenberger C, Heyman SN, Rosen S, et al. Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia. Kidney Int, 2005,67;531~542.
[10] Matsumoto M, Makino Y, Tanaka T, et al. Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats .J American Society of Nephrology , 2003,14(7):1825~1832.
[11] Katori M, Buelow R, Ke B, et al. Heme oxygenase-1 overexpression protects rat hearts from cold ischemia-reperfusion injury via an antiapoptotic pathway. Transplantation, 2002, 73(2):287~292.
[12] Fondevila C, Shen XD, Tsuchiyashi S, et al. Biliverdin therapy protects rat livers from ischemia and reperfusion injury. Hepatology, 2004, 40(6): 1333~1341.
[13] Nakao A, Kimizuka K, Stolz DB, et al. Protective effect of carbon monoxide inhalation for cold-preserved small intestinal grafts. Surgery, 2003, 134(2):285~292.
[14]黄越芳,庄思齐.去铁胺对新生大鼠缺氧缺血性脑损伤的保护作用.广东医学, 2003,24:696~698.
[15] Yonezawa M, Back SA , Gan X,et al. Cystine deprivation induces oligodendroglial death: rescue by free radical scavengers and by a diffusible glial factor. J Neurochem, 1996 , 67 (2) :566~573.
[16] Jones NM, Bergeron M. Hypoxic preconditioning induces changes in HIF– 1 target genes in neonatal rat brain. J Cereb Blood Flow Metab ,2001 ,21(9) :1105~1114.
[17] Vartiainen N , Keksa-Goldsteine V , Goldsteins G, et al. Aspirin inhibits p44/42 mitogen-activated protein kinase and is protective against hypoxia/reoxygenation neuronal damage. Sroke,2003,34(3):752~757.
[18] Sharp FR, Bergeron M, Bernaudin M. Hypoxia-inducible factor in brain. Adv Exp Med Biol,2001,502 :273~291.
[19] Bergeron M, Gidday JM ,Yu AY, et al. Role of Hypoxia-inducible factor-1 in hypoxia- induced ischemic tolerance in neonatal rat brain. Ann Neurol ,2000,48(3) :285~296.
[20]张力,陈珊琳.腺苷对大鼠缺血性急性肾衰竭的干预作用.实用儿科临床杂志, 2006,21(5):290~291.
[21] Vyacheslav Y. Melnikov SF, Britta SM, et al. Neutrophilindependent mechanisms of Caspase-1 and IL-18-mediated ischemic acute tubular necrosis in mice. J ClinInvest, 2002, 110: 1083~1091.
[22]张萱,韩丽姝,徐晋,等.肾缺血再灌注损伤和丹参的保护作用的实验研究.解剖科学进展,1996,2(3):269~272.
[23] Raff U, Schneider R, Gambaryan S,et al . L-Arginine does not affect renal morphology and cell survival in ischemic acute renal failure in rats. Nephron Physiol, 2005,101(3): 39~50.
[24] Sheridan AM, Bonventre JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens ,2000,9 :427 ~ 434.
[25] Bernhardt WM, Campean V, Kany S, et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol, 2006, 17(7):1970~1978.
[26] Reiter RJ, Poeggeler B, Dun-xian, et al. Antioxidant capacity of melatonin: Anovelactionnotrequiringre-ceptor. NeuroendocrinolLett, 1993,15:103~116.
[27] Marshall KA, Reiter RJ, Poeggeler B,et al. Evaluation of the antioxidant activity of melatonin in vitro. Free Radical Biology&Medicine, 1996,21(3): 307~315.
[28] Srinivas V, Zhang LP, Zhu XH, et al. Characterization of an oxygen/ redox -dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins. Biochem Biophys Res Commun, 1999, 260(2):557~561.
[29] Tanimoto K, Makino Y, Pereira T, et al. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J, 2000, 19(16):4298~4309.
[30] Min JH, Yang H, Ivan M, et al. Structure of an HIF-lalpha -pVHL complex: hydroxyproline recognition in signaling. Science, 2002 ,296(5574):1886~1889.
[31] Lando D, Peet DJ, Whelan DA. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science, 2002 ,295(5556):858~861.
[32] Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA binding activity:implications for models of hypoxia signal transduction. Blood. 1993,82:3610~3615.
[33] Wang GL, Jiang BH, Rue EA, Semenza Gh. Hypoxia-inducible factor 1 is a basic-helix- loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995,92:5510~5514.
[34] Zaman K, Ryu H, Hall D, et al.Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, and erythropoietin. J Neurosci,1999, 19:9821~9830
[35] Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor -1αis mediated by an O2-dependent degradation domain via theubiquitin-proteasome pathway. Proc Natl Acad Sci, USA. 1998:7987~7992.
[36] Kallio PJ, Wilson WJ, O'Brien S, Makino Y. and Poellinger L. Regulation of the hypoxia-inducible transcription factor-1 a by the ubiquitin-proteasome pathway. J Biol Chem, 1999, 274: 6519~6525.
[37] Ivan M.,et al.HIF-1a targeted for VHL-mediated destruction by praline hydroxylation: implications for O2sensing. Science,2001,292:464~468.
[38] Bruick RK, Mcknighy SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001,294:1337~1340.
[39] McNeill LA, Hewitson KS, Gleadle JM, et al.The use of dioxygen by HIF prolyhydroxylase l (PHD1).Bioorg Medical Chem Lett. 2002,12: 1547~1550.
[40] Min JH, Yang HF, Ivan M, et al. Structrue of an HIF-1 a–pVHL complex: Hydroxyproline recognition in signaling. Science. 2002, 296:1886~1889.
[41] Londo D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes&Development. 2002,16:1466~1471.
[42] Hewitson KS, Mcneill LA, Riordan MV, Tian YM, et al. Hypoxia-inducible factor(HIF) asparagines hydroxylase is identical to factor inhibiting HIF(FIH) and is related to the cupin structural family. J Biol Chem. 2002, 277: 26351~26355.
[43] Dames SA, Martinet YM, De Guzman RN, et al. Structural basis for HIF a/CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci. 2002, 99: 5271~5276.
[44] Foresti R, Goatly H, Green CJ, et al. Role of heme oxygenase-1 in hypoxia- reoxygenation: requirement of substrate heme to promote cardioprotection. Am J Physiol Heart Circ Physiol, 2001,281(5): H1976~1984.
[45] Katori M, Anselmo DM, Busuttil RW, et al. A novel strategy against ischemia and reperfusion injury: cytoprotection with heme oxygenase system.Transpl Immunol, 2002,9(2-4):227~233.
[46] Horikawa S, Yoneya R, Nagashima丫et al. Prior induction of heme oxygenase-1 with glutathione depletory ameliorates the renal ischemia and reperfusion injury in the rat. FEBS Lett, 2002, 510(3): 221~224.
[47] Vulapalli SR, Chen Z, Chua BH, et al. Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis. Am J Physiol Heart Circ Physiol, 2002 283(2): H688~694.
[48] Guo X, Shin VY, Cho CH. Modulation of heme oxygenase in tissue injury and its implication in protection against gastrointestinal diseases. Life Sci, 2001, 69(25-26): 3113~3119.
[49] Stefan G, Melina NK, Roland B, et al. Inhibition of ischemia reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt protoporphyrin for the induction of heme oxygenase-1. Transplatation, 2002,74:591~598.
[50] Mahin D, Maines. Spin Trap(N-t-butyl- a -phenylnitrone)-mediated suprainduction of heme oxygenase-1 in kidney ischemia/reperfusion model:Role of the oxygenase in protection against oxidative injury.The J Pharmacology and Experimental 1999; 291(2): 911~920.
[51] Elbirt KK, Whitmarsh AJ, Davis RJ, et al. Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells. J Biol Chem, 1998, 273:8922~8931.
[52] Hiroko S, Toru T, Tsutomu S, et al. Protective effect of heme oxygenase induction in ischemic acute renal failure. Crit Care Med, 2000,28:809~817.
[53] Akagi R, Takahashi T, Sassa S. Fundamental role of heme oxygenase in the protection against ischemic acute renal failure. Jpn J Pharmacol, 2002, 88(2): 127~132.
[54] Ishizuka S, Nagashima Y, Numata M, et al. Regulation and immunohistochemical analysis of stress protein heme oxygenase-1 in rat kidney with myoglobinuric acute renal failure. Biochem Biophys Res Commun, 1997,240:93~98.
[55] Nath KA, Balla G,Vercellotti GM, et al. Induction of heme oxygenase is arapid,protective response in rhabdomyolysis in the rat. J Clin Invest, 1992, 90:267~270.
[56]Prass K, Ruscher K, Karsch M, et al. Desferrioxamine induced delayed tolerance against cerebral ischemia in vivo and in vitro. J Cereb Blood Flow Metab,2002, 22 (5) :520~525.
[57]Yang ZZ, Zou AP. Transcriptional regulation of heme oxygenases by HIF-lalpha in renal medullary interstitial cells. Am J Physiol Renal Physiol,2001,281 (5): 900~908.
[58]章斌,陈楠,邢静萍,等.缺血再灌注肾损伤中血红素加氧酶-1的表达及其意义.中华肾脏病杂志,2004,20:214~215.
[1] Florian T, Zhuma H, Kathleen W,et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol, 2005, 289: 31~42.
[2]Makiko M, Yuichi M, Tetsuhiro T,et al. Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats. American Society ofNephrology ,2003,14:1825~1832.
[3]王晗.缺氧诱导因子—1与细胞凋亡.国外医学.生理病理学与临床分册,2005, 25 (1):52~56.
[4]Rosenberger C,Heyman SN,Rosen S,et al .Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia.Kidney lnt,2005,67(2):531~542.
[5]Rosenbergerc,Mandriota S,Jtirgensen S,et a1. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol,2002,13(7):1721~1732.
[6]Matsumoto M,Makino Y,Tanaka T,et a1.Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats.J Am Soc Nephrol,2003,14:1825~1832.
[7]Shimizu H,Takahashi T,Suzuki T,et a1.Protective effect of heme oxygenase induction in ischemic acute renal failure.Crit Care Med, 2000,28:809~817.
[8]平蕾,沈霞,耿德勤等.促红细胞生成素对大鼠局灶性脑缺血CAPSASE—3蛋白的影响.神经疾病与精神卫生,2004,4(5):337~340.
[9]Junk AK, Mammis A, Savitz SI, et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci US A,2002,99 (16): 10659~10664.
[10]Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the H IF system. NatMed, 2003, 9 (6):677~ 684.
[11]ZhangQZ, Zhang ZF, Rao JY, et al. Treatment with siRNA and antisense oligonucleotides targeted to H IF-1αinduced apoptosis in human tongue squamous cell carcinomas. Int J Cancer, 2004,111: 849~ 857.
[12]Hellwig-Burgel T, Stiehl DP, Katschinski DM, et al. VEGF Production by primary human renal proximal tubular cells: requirement of HIF-1, PI32 -kinase and MAPKK-1 signaling. Cell Physiol Biochem,2005,15(1-4):99~108.
[13]Kanellis J,Mudge SJ,Fraser S, et al. Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury . Kidney Int , 2000 ,57 (6) : 2445~2456.
[14]Cozzi A, Levi S, Corsi B, et al. Role of iron and ferritin in TNFalpha-induced apoptosis in HeLa cells. FEBS Lett, 2003, 537(1-3):187~92.
[15] Graca-Souza AV, Arruda MA, de Freitas MS, et al. Neutrophil activation by heme: implications for inflammatory processes. Blood, 2002, 99(11):4160~4165.
[16] Matsumoto M, Makino Y, Tanaka T, et al. Induction of Renoprotective Gene Expression byCobalt Ameliorates Ischemic Injury of the Kidney in Rats .J American Society of Nephrology , 2003,14(7):1825~1832.