冬虫夏草对大鼠肾缺血再灌注模型肾组织HIF-1α及NGAL表达的影响
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摘要
目的：
观察大鼠肾缺血-再灌注后尿NGAL浓度、肾组织HIF-1α和NGAL的表达以及冬虫夏草干预后对其的影响,进一步探讨冬虫夏草的肾保护作用机制。
方法：
将45只健康雄性SD大鼠随机分为假手术组(sham组,n=15)、缺血-再灌注组(I／R组,n=15)和冬虫夏草组(CS组,n=15),3组组内再按24h、48h、72h 3个时间点分成3小组,每组5只。用摘除右肾后夹闭左肾蒂1h恢复再灌注的方法建立肾I／R模型,sham组摘除右肾后未夹闭左肾蒂,术后每日予以生理盐水(2ml／d)灌胃,I／R组和冬虫夏草组分别在术后予以生理盐水(2ml／d)和冬虫夏草提取液(5.0g／kg.d)灌胃,在相应时间点处死大鼠。检测各组大鼠肾功能(BUN, Scr)、比色法检测各组大鼠的尿NAG酶、ELISA法检测各组大鼠尿NGAL浓度、HE染色观察大鼠肾小管间质病理变化,并用肾小管间质半定量计分法分析各组大鼠病理损伤情况、RT-PCR法观察各组大鼠肾组织中HIF-1αmRNA的表达水平、免疫荧光共聚焦法观察各组大鼠肾组织HIF-1α和NGAL蛋白的表达情况。
结果：
1.与假手术组相比,缺血-再灌注组大鼠的血清BUN及Scr水平增高,尿NAG酶及NGAL增多,均于24h达高峰,之后逐渐下降,72h仍较高,差异均有统计学意义(P<0.05)。假手术组大鼠肾小球及小管间质均正常,无明显病理改变；肾缺血-再灌注组出现肾小管上皮细胞普遍肿胀,可见小管扩张,管腔管型,刷状缘消失,部分上皮细胞变性坏死等改变,肾小球无明显病理改变。
2.与假手术组相比较,缺血-再灌注组各时间点大鼠肾组织HIF-1αmRNA及蛋白、NGAL蛋白的表达均明显升高,差异有统计学意义(P<0.05)。
3.与缺血-再灌注组相比较,冬虫夏草组各时间点的BUN和Scr水平下降、尿NAG酶和尿NGAL浓度降低、肾组织NGAL蛋白的表达下调、HIF-1αmRNA及其蛋白的表达上调。肾小管病理半定量计分显示冬虫夏草组较缺血再灌注组小管间质损伤明显改善,差异均有统计学意义(P<0.05)。
结论：
1.肾缺血-再灌注大鼠模型病理改变表现为肾小管及肾间质受损,与急性肾损伤病理改变特征相符合。
2.肾缺血-再灌注后尿NGAL水平增高,与尿NAG及肾小管间质损伤程度成正相关,提示NGAL可能是急性肾损伤时肾小管损伤特异性的生物标志物。
3.冬虫夏草可能通过改善肾组织中HIF-1α与NGAL的异常表达而达到肾保护作用。
Objective:
To observe the level of urinary NAG,the expressions of HIF-la and NGAL in rats kidney following renal ischemia and reperfusion,prior to and after treatment with Cordyceps sinensis(CS),in a bid to explore the mechanism of CS against I/R injury.
Method:
45 healthy male Sprague-Dawley rats were randomly divided into three groups:Sham group(n=15),renal ischemia and reperfusion model group(n=15),and Cordyceps Sinensis treatment group(n=15).The rat models were established using the following method:First,the right kidney was excised.Then,the left renal pedicle was clamped for 60 min to achieve ischemia. Finally, reperfusion was accomplished by releasing the clamps.The rats in the Sham operation group were only subjected to excision of the right kidney without undergoing clamping of the left renal pedicle.The rats in the Sham group and renal ischemia/reperfusion model group were fed by intragastric administration of saline (2ml/d),and rats from the treatment group were treated by intragastric administration of Cordyceps Sinensis(5.0g/kg.d), The rats were sacrificed at 24h,48h,72h respectively after reperfusion and urinary N-acetyl-β-D-glucosaminidase (NAG) level measured,renal function in rats detected,and the pathological changes were observed using hematoxylin and eosin(HE) staining.The extent of histopathological damage in the tubulointerstitium was assessed semi-quantitatively by means of a scoring method. We determined urinary NGAL levels of the rats by the ELISA method,the expression of HIF-1αmRNA by RT-PCR,and the expressions of HIF-1αand NGAL proteins by Confocal immunofluorescence.
Results
1. Compared to the Sham group,the levels of BUN、Scr、urinary NAG and urinary NGAL were increased in the Ischemia and Reperfusion group, reached a peak at 24h after reperfusion and slowly declined at 48h and 72h,the differences being statistically significant (P<0.05).We found that the urinary NGAL level had positive correlations with urinary NAG. Glomerular and tubulointerstitial areas in the Sham group did not show any pathological change. Induced pathological changes included tubular cell necrosis,focal areas of proximal tubular dilation,distal tubular casts,effacement and loss of proximal tubule brush border etc.
2.Compared to the Sham group, the expressions of HIF-1αand NGAL in the kidney tissues of Ischemia and Reperfusion group increased, the differences being statistically significant (P<0.05).
3.Cordyceps Sinensis can lower the level of urinary NAG、urinary NGAL and the expression of NGAL protein in the kidney tissues.It up-regulates the expressions of HIF-1αmRNA and protein in the kidney tissues whilst attenuating the pathological changes.Compared to the Ischemia and Reperfusion group,the differences were statistically significant (P<0.05)
Conclusion
1.Renal ischemia-reperfusion injury in rats can lead to pathological changes in renal tubular epithelial cells and renal interstitial damage,which are consistent with the pathological features of acute kidney injury(AKI).
2. The level of urinary NAGL increased following renal ischemia and reperfusion, which kept positive correlation with the level of urinary NAG and pathological changes,suggesting that urinary NGAL may function as a urinary biomarker for specific detection of tubular injury in AKI.
3.Cordyceps Sinensis can attenuate renal ischemia/reperfusion-induced AKI. Its mechanism may be associated with up-regulating the expression of HIF-1αin the kidney tissue and down-regulating the expression of NGAL in the kidney tissue.
观察大鼠肾缺血-再灌注后尿NGAL浓度、肾组织HIF-1α和NGAL的表达以及冬虫夏草干预后对其的影响,进一步探讨冬虫夏草的肾保护作用机制。
方法：
将45只健康雄性SD大鼠随机分为假手术组(sham组,n=15)、缺血-再灌注组(I／R组,n=15)和冬虫夏草组(CS组,n=15),3组组内再按24h、48h、72h 3个时间点分成3小组,每组5只。用摘除右肾后夹闭左肾蒂1h恢复再灌注的方法建立肾I／R模型,sham组摘除右肾后未夹闭左肾蒂,术后每日予以生理盐水(2ml／d)灌胃,I／R组和冬虫夏草组分别在术后予以生理盐水(2ml／d)和冬虫夏草提取液(5.0g／kg.d)灌胃,在相应时间点处死大鼠。检测各组大鼠肾功能(BUN, Scr)、比色法检测各组大鼠的尿NAG酶、ELISA法检测各组大鼠尿NGAL浓度、HE染色观察大鼠肾小管间质病理变化,并用肾小管间质半定量计分法分析各组大鼠病理损伤情况、RT-PCR法观察各组大鼠肾组织中HIF-1αmRNA的表达水平、免疫荧光共聚焦法观察各组大鼠肾组织HIF-1α和NGAL蛋白的表达情况。
结果：
1.与假手术组相比,缺血-再灌注组大鼠的血清BUN及Scr水平增高,尿NAG酶及NGAL增多,均于24h达高峰,之后逐渐下降,72h仍较高,差异均有统计学意义(P<0.05)。假手术组大鼠肾小球及小管间质均正常,无明显病理改变；肾缺血-再灌注组出现肾小管上皮细胞普遍肿胀,可见小管扩张,管腔管型,刷状缘消失,部分上皮细胞变性坏死等改变,肾小球无明显病理改变。
2.与假手术组相比较,缺血-再灌注组各时间点大鼠肾组织HIF-1αmRNA及蛋白、NGAL蛋白的表达均明显升高,差异有统计学意义(P<0.05)。
3.与缺血-再灌注组相比较,冬虫夏草组各时间点的BUN和Scr水平下降、尿NAG酶和尿NGAL浓度降低、肾组织NGAL蛋白的表达下调、HIF-1αmRNA及其蛋白的表达上调。肾小管病理半定量计分显示冬虫夏草组较缺血再灌注组小管间质损伤明显改善,差异均有统计学意义(P<0.05)。
结论：
1.肾缺血-再灌注大鼠模型病理改变表现为肾小管及肾间质受损,与急性肾损伤病理改变特征相符合。
2.肾缺血-再灌注后尿NGAL水平增高,与尿NAG及肾小管间质损伤程度成正相关,提示NGAL可能是急性肾损伤时肾小管损伤特异性的生物标志物。
3.冬虫夏草可能通过改善肾组织中HIF-1α与NGAL的异常表达而达到肾保护作用。
Objective:
To observe the level of urinary NAG,the expressions of HIF-la and NGAL in rats kidney following renal ischemia and reperfusion,prior to and after treatment with Cordyceps sinensis(CS),in a bid to explore the mechanism of CS against I/R injury.
Method:
45 healthy male Sprague-Dawley rats were randomly divided into three groups:Sham group(n=15),renal ischemia and reperfusion model group(n=15),and Cordyceps Sinensis treatment group(n=15).The rat models were established using the following method:First,the right kidney was excised.Then,the left renal pedicle was clamped for 60 min to achieve ischemia. Finally, reperfusion was accomplished by releasing the clamps.The rats in the Sham operation group were only subjected to excision of the right kidney without undergoing clamping of the left renal pedicle.The rats in the Sham group and renal ischemia/reperfusion model group were fed by intragastric administration of saline (2ml/d),and rats from the treatment group were treated by intragastric administration of Cordyceps Sinensis(5.0g/kg.d), The rats were sacrificed at 24h,48h,72h respectively after reperfusion and urinary N-acetyl-β-D-glucosaminidase (NAG) level measured,renal function in rats detected,and the pathological changes were observed using hematoxylin and eosin(HE) staining.The extent of histopathological damage in the tubulointerstitium was assessed semi-quantitatively by means of a scoring method. We determined urinary NGAL levels of the rats by the ELISA method,the expression of HIF-1αmRNA by RT-PCR,and the expressions of HIF-1αand NGAL proteins by Confocal immunofluorescence.
Results
1. Compared to the Sham group,the levels of BUN、Scr、urinary NAG and urinary NGAL were increased in the Ischemia and Reperfusion group, reached a peak at 24h after reperfusion and slowly declined at 48h and 72h,the differences being statistically significant (P<0.05).We found that the urinary NGAL level had positive correlations with urinary NAG. Glomerular and tubulointerstitial areas in the Sham group did not show any pathological change. Induced pathological changes included tubular cell necrosis,focal areas of proximal tubular dilation,distal tubular casts,effacement and loss of proximal tubule brush border etc.
2.Compared to the Sham group, the expressions of HIF-1αand NGAL in the kidney tissues of Ischemia and Reperfusion group increased, the differences being statistically significant (P<0.05).
3.Cordyceps Sinensis can lower the level of urinary NAG、urinary NGAL and the expression of NGAL protein in the kidney tissues.It up-regulates the expressions of HIF-1αmRNA and protein in the kidney tissues whilst attenuating the pathological changes.Compared to the Ischemia and Reperfusion group,the differences were statistically significant (P<0.05)
Conclusion
1.Renal ischemia-reperfusion injury in rats can lead to pathological changes in renal tubular epithelial cells and renal interstitial damage,which are consistent with the pathological features of acute kidney injury(AKI).
2. The level of urinary NAGL increased following renal ischemia and reperfusion, which kept positive correlation with the level of urinary NAG and pathological changes,suggesting that urinary NGAL may function as a urinary biomarker for specific detection of tubular injury in AKI.
3.Cordyceps Sinensis can attenuate renal ischemia/reperfusion-induced AKI. Its mechanism may be associated with up-regulating the expression of HIF-1αin the kidney tissue and down-regulating the expression of NGAL in the kidney tissue.
引文
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[1]Smith H:The Kidney:Structure and Functionin Health and Disease. London, Oxford University Press,1964.
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[1]Smith H:The Kidney:Structure and Functionin Health and Disease. London, Oxford University Press,1964.
[2]Wamoch DG. Towards a definition and classification ofacute kidney injury [J]. J Am Soc Nephrol,2005,16(11):3149—3150
[3]Ronco C, Levin A, Warnock DG, et al. Improving outcomes from acute kidney injury (AKI):Report on an initiative [J]. Int J Artif Organs,2007,30(5):373-376
[4]Devarajan P:Emerging biomarkers of acute kidney injury. Contrib Nephrol. Basel, Karger,2007, vol 156, pp 203-212.
[5]Vaidya VS, Ferguson MA, Bonventre JV:Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol 2008; 48:463-493.
[6]Herget-Rosenthal S, Poppen D, Husing J, et al. Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem 2004,50 (3):552-558
[7]Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C [J].Kidney Int,2004,66 (3):1115—1122.
[8]吴亚君,施岚,范亚平,等.尿液西司他汀测定与肾小管损害的相关性研究[J].放射免疫学杂志,2004,17(3)：232—233.
[9]Bezerra CN, Girardi AC, Carraro-Lacroix LR, et al.Mechanisms underlying the long-term regulation of NHE3 by parathyroid hormone. Am J Physiol Renal Physiol,2008,5 (3):25.
[10]Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase associated lipocalin as a novel early urinary biomarker for ischemic renal injury[J].J Am Soc Nephrol,2003,14(10):2534-2543
[11]Mishra J, Mori K, Ma Q, et al. Amelioration of ischemic acute renal injury by neutrophil-gelatinase-associated-lipocalin[J].JAmSocNephrol,2004,15(12):30 73-3082
[12]Mori K, Lee H T, Rapoport D, et al. Endocytic delivery of lipocalin siderophore-iron complex rescues the kidney from ischemia-reperfusion injury[J].J Clin Invest.2005,115(3):610-621
[13]Bennett M, Dent CL, Ma Q, Dastrala S, GrenierF, Workman R, Syed H, Ali S, Barasch J,Devarajan P:Urine NGAL predicts severity of acute kidney injury after cardiac surgery:a prospective study. Gin J Am Soc Nephro12008; 3: 665-673.
[14]Ronco C:N-GAL:Diagnosing AKI as soonas possible. Crit Care 2007; 11:173
[15]Parikh CR, Jani A, Melnikov VY, et al. Urinary interleukin-18 is a marker of human acute tubularnecrosis. Am J Kidney Dis,2004,43 (3):405-414.
[16]Kwon O, Molitoris BA, Pescovitz M, et al. Urinary actin, interleukin-6, and interleukin-8 may predict sustained ARF after ischemic injury in renal allografts. Am J Kidney Dis,2003,41 (5):1074-1087.
[17]Haase M, Bellomo R, Story D, Davenport P.Haase-Fielitz A:Urinary interleukin-18 does not predict acute kidney injury after adult cardiac surgery: a prospective observational cohort study. Crit Care 2008; 12:R96.
[18]Zhang Z, Humphreys BD, Boruentre JV. Shedding of the urinary biomarkei kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region [J]. J Am Soc Nephrol,2007,18(10):2701-2711.
[19]Han WK, Bailly V, Abichandani R, et al. Kidney injuryMolecule-1 (KIM-1):a novel biomarker for human renal proximal tubule injury. Kidney Int,2002,62 (1):237-244.
[20]Vaidya VS, Ramirez V, Ichimura T, BobadillaNA, Bonventre-JV:Urinary kidney injury molecule-1:a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 2006; 290:F517-F529.
[21]. Vaidya VS,Ramirez V, Ichimura T, et al. Urinary kidneyinjury molecule-1, a sensititive quantitativebiomaiker for early detection of kidney tubular injury. Am J Physiol Renal Physiol,2006,290 (2):517-529.
[22]吉程程,梅长林,急性肾损伤定义、诊断及防治进展[J]中国血液净化,2008,vol.7.NO12：47
[23]Garwood S, Swamidoss CP, Davis EA, et al. A caseseries of low-dose fenoldopam in seventy cardiac surgicalpatients at increased risk of renal dysfunction [J]. J Cardiothorac Vasc Anesth,2003,17(1):17-21
[24]Kim YK, Choi TR, Kwon CH, et al. Beneficial effect ofpentoxifylline on cisplatin-induced acute renal failure in rabbits[J]. Ren Fail,2003,25(6):909-922.
[25]Chitalia VC, Almeida AF, Rai H, et al. Is peritoneal dialysis adequate for hypercatabolic acute renal failure in developing countries芽[J].Kidney Int, 2002,61 (2):747-757.
[26]Bagshaw SM, Berthiaume LR, Delaney A,et al.Continuousversus intermittent renal replacement therapy for critically ill patients with acute kidney injury:a metaanalysis [J].Crit Care Med,2008,36 (2):610-617.
[27]Kellum JA, Angus DC, Johnson JP, et al. Continuous versus intermittent renal replacement therapy:a metaanalysis [J].Intensive Care Med,2002, 28 (1):29-37.
[28]Van Biesen W, Vanholder R, Lameire N. Dialysis strategies in critically ill acute renal failure patients [J]. Curr Opin Crit Care,2003,9(6):491-495.
[29]Fliser D, Kielstein JT. Technology Insight:treatment of renal failure in the intensive care unit with extendeddialysis[J]. Nat Clin Pract Nephrol,2006,2(1):32-39.
[30]Saudan P, Niederberger M, De Seigneux S, et al. Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure [J]. Kidney Int,2006,70(7):1312-1317.
[31]Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure [J].N Engl J Med,2002,346(5):305-310.