肾损伤分子-1表达在移植肾损伤中的变化和意义
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摘要
肾损伤分子（KIM-1）是新颖、特异性高的判断肾小管损伤的生化指标，尿液和组织标本中均可以检测出其表达；当肾近曲小管发生急慢性损伤时，KIM-1在肾小管细胞中表达，成为凋亡细胞被吞噬与被清除的受体；KIM-1可能在肾小管损伤和修复过程中发挥重要病理生理作用。在移植肾脏中，肾小管损伤的相关因素有缺血、免疫抑制剂毒性、急性排斥反应等，各种因素联合作用或单独作用均可以导致慢性移植肾肾病，最终导致移植肾脏丢失。肾组织穿刺活检，是判断和识别移植肾脏损伤的重要检测手段。肾穿标本病理形态学观察可见到：肾小管上皮刷状缘的改变、上皮细胞的凋亡/坏死、小管纤维化/萎缩、上皮脱落等，但因形态诊断是存在主观因素的影响，需要寻求一个早期敏感度高的客观判断肾小管轻微损伤的指标。
本选题以KIM-1为研究的核心，探索其在移植肾损伤中的变化和意义。
我们选取2009年-2011年69例移植肾穿刺活检的组织标本，应用免疫组织化学方法标记移植肾组织中KIM-1的表达情况，分析移植肾组织中KIM-1表达水平和其他血液生化指标的关系、移植肾组织中KIM-1表达与移植肾功能的相关性。结果显示：（1）在不同病理诊断分组中可见KIM-1在近端小管上皮出现不同程度的表达；（2）在急性T细胞性排斥反应中，KIM-1表达量随Banff07分级升高而呈现增高趋势，同时KIM-1表达水平与小管炎严重程度相一致。在小管炎出现可见的形态改变之前，KIM-1蛋白已出现可见的阳性表达。（3）慢性活动性抗体介导排异反应中，KIM-1呈强阳性表达，强烈提示活动性排异反应所致肾损伤的存在；（4）在交界性病变时，KIM-1出现不同程度阳性表达，提示肾小管上皮处于损伤状态；（5）未见排斥反应发生和免疫抑制剂中毒组，27.27%（3/11）病例血肌酐在正常范围内，但肾组织中KIM-1呈弱阳性表达。本研究表明：（1）在移植肾组织中KIM-1表达水平与移植肾损伤程度呈正相关，提示肾小管细胞损伤存在。（2）在未见血生化指标升高提示肾损伤时、未见形态学可见肾损伤改变时、未见肾小管炎症反应时，均可见KIM-1蛋白在肾小管上皮细胞表达，提示KIM-1蛋白在移植肾活检组织中表达可以成为早期、敏感、特异判定肾小管上皮细胞损伤的生化指标。
本研究通过采用ELISA方法检测肾移植患者血清中KIM-1的表达，研究和探索早期血清中与组织内KIM-1的表达能否成为早期判断移植肾功能异常的应用指标。结果表明：（1）在移植肾患者血清中KIM-1表达的增强可以提示移植肾损伤程度的强弱。（2）慢性活动性排斥造成的损伤可以出现血清KIM-1的高表达，提示移植肾脏功能状态恶化。（3）早期血清中肾损伤分子-1水平升高可能成为提示移植肾功能状态的生化指标。
在本次实验研究中，采用体外实验方法研究环孢素损伤肾小管细胞后导致其产生KIM-1的表达，并初步探索其中机制，寻找保护和延缓环孢素对移植肾损伤的药物。
在实验中首先建立环孢素损伤肾近曲小管上皮细胞的体外研究模型，采用MTT实验方法筛选环孢素的损伤作用的适宜浓度；采用MTT实验法筛选可能的药物干预改善环孢素对肾小管上皮细胞的损伤；筛选出促红细胞生成素（EPO）可以保护肾小管细胞减少环孢素对细胞的损伤。采用丝裂原活化蛋白激酶系统阻断剂(p38通路阻断剂SB202190、ERK1/2通路阻断剂PD98059)，阻断相应酶的表达，以期推测生化过程发生的机制。采用ELISA方法鉴定KIM-1在细胞上清液中的表达，统计KIM-1表达量的变化。采用流式细胞仪测定在环孢素损伤肾小管中细胞凋亡发生特点。
环孢素使肾近曲小管细胞损伤时KIM-1表达升高并导致细胞凋亡，在这一过程中丝裂原活化蛋白激酶中的p38通路、ERK1/2通路在其中发挥作用。阻断以上2条通路可以减少CsA所致HKC细胞的凋亡比率（P<0.05），增加活细胞比率（P<0.05），减少细胞的坏死比率（P<0.05），同时减少KIM-1蛋白的表达量（P<0.05）。加入EPO可以减少HKC细胞在CsA作用下产生KIM-1蛋白（P<0.05）；选用EPO15U/ml和30U/ml进行实验，随EPO作用量的增加，可以减少HKC细胞在CsA损伤中产生KIM-1的量值，提示EPO可以拮抗CsA对肾小管上皮的损伤，减少CsA所致肾小管上皮细胞凋亡和坏死的发生。
肾损伤分子-1在移植肾中的表达和变化具有重要的研究价值，可以成为判定移植肾损伤早期、敏感、特异性判定肾小管上皮细胞损伤的生化指标；早期血清中肾损伤分子-1水平升高可能成为提示移植肾功能状态的生化指标。环孢素使肾近曲小管细胞损伤时KIM-1表达升高，在这一过程中丝裂原活化蛋白激酶中的p38通路、ERK1/2通路在其中起到作用。阻断p38通路、阻断ERK1/2通路、加入EPO三种因素均可以减少肾小管细胞在CsA作用下产生KIM-1蛋白，有效保护和延缓环孢素对移植肾小管上皮损伤的过程。本次选题的实验结果与结论，为肾损伤分子-1在移植肾领域中的应用提供有利的基础实验依据，同时为减少环孢素对移植肾损伤方面继续探索提供可参考的实验模型与有效的实验药物。
Kidney injury molecule-1(KIM-1) is a new specific biomarker of proximal tubule injurythat can be measured both in urine and kidney tissue samples. It is an apoptotic-cellphagocytosis and scavenger receptor that is most highly upregulated in proximal tubularepithelium in acute and chronic kidney injury. Also, much attention has been paid to itspossible pathophysiological role in modulation of tubular damage and repair. In renalallografts, tubular injury associated with ischemia, nephrotoxicity secondary toimmunosuppressive medication, and/or acute cellular rejection can lead to chronic allograftnephropathy and eventual graft failure. Pre-renal and post-renal factors contributing to renalfailure are not always easily distinguished from intrarenal injury in allograft recipients.Changes in kidney epithelial cell morphology in allograft biopsies can vary from no orminimal histologic changes of proximal tubules to diminished brush borders, apoptosis and/ornecrosis, dilated tubules, and sloughed epithelial cells in the tubular lumina. A pathologicdiagnosis of acute tubular injury is often quite subjective. A sensitive tissue biomarker oftubular injury, which can be used to identify or confirm the presence of epithelial cell injurywhen pathological changes are minimal would be very helpful in the evaluation of biopsyspecimens.
The topic around the KIM-1as the core of the study, we explore the significance of thechange and its expression in the renal allograft injury.
A total of69patients who underwent kidney transplantation between2009-2011wereenrolled in this study. KIM-1expression was detected by immunohistochemical methods andthe association of KIM-1and blood biochemical indexes was analyzed. KIM-1expressionincreased as Banff2007classification grade increased and was positively correlated withtubular inflammation severity in the acute T-cell rejection group. Moreover, KIM-1expression was strongly positive in the chronic active antibodymediated rejection group.Interestingly, KIM-1was weakly positive in the normal group without obvious acute rejection and injury of immunosuppressant toxicity. In this group,27.27%(3/11) of the cases withnormal serum creatinine level showed weakly positive KIM-1expression in their renal tissues.KIM-1expression level is positively correlated with renal allograft damage and tubular cellinjury. KIM-1is expressed in tubular epithelial cells before blood biochemical indexesbecome elevated and morphological changes occur. KIM-1expression is an early, sensitive,and specific biomarker to determine renal tubular epithelial cell injury in renal allograft tissue.
Serum KIM-1expression was detected by ELISA methods, we explore the significanceof the change and its expression in the renal allograft injury.The results showed that:(1) Theserum KIM-1expression is associated with renal allograft injury.(2) Chronic active rejectioncan occur resulting the serum KIM-1expression, suggesting that graft worsening renalfunction status.(3) Early serum kidney injury molecule-1levels may be the new biochemicalmarker for renal allograft function.
In this experimental study, We make use of cyclosporine in renal tubular epithelial injuryin vitro, which produces KIM-1expression and initial exploration of which mechanism tofind drugs which can protect and delay renal allograft injury by cyclosporine.
In the experiment, renal proximal tubule epithelial cells was injuryed by cyclosporine invitro, suitable concentration injury screening of cyclosporine was determined by using the MTTassay method; screening using the MTT assay method of drug intervention may improve renalcyclosporine tubular epithelial cell injury; screened erythropoietin (EPO) can protect renaltubular cells. Using mitogen-activated protein kinase system blockers (p38pathway inhibitorSB202190, ERK1/2pathway inhibitor PD98059), blocking the expression of thecorresponding enzyme mechanisms and biochemical processes occurring to speculate. ELISAusing the method of identifying the expression of KIM-1in the cell supernatant, the KIM-1expression level of statistical variation. Characteristics of the cells was measured by flowcytometry apoptosis in renal tubular injury in cyclosporine
When the renal tubule cell was injured by Cyclosporine, KIM-1expression was increased,in the process of mitogen-activated protein kinase in the p38pathway, ERK1/2pathway playsa role. Blocking these two paths can be reduced HKC CsA-induced apoptosis rate (P <0.05),the ratio of living cells increased (P <0.05), reducing the ratio of necrotic cells (P <0.05), while reducing the KIM-1expression (P <0.05). EPO can be added to reduce the HKC cellsKIM-1protein (P <0.05); optional EPO15U/ml and30U/ml experiment with the effect ofincreasing the amount of EPO may be reduced KIM-1expression, suggesting that EPO mayantagonize CsA on renal epithelial damage, reduce the occurrence of CsA-induced tubularepithelial cell apoptosis and necrosis.
Kidney injury molecule-1expression and changes in renal allograft has importantresearch value, could be early、sensitive、specific determination of renal tubular epithelial cellinjury and biochemical marker for renal allograft injury.The serum kidney injury molecule-1levels may become early biochemical markers. When the renal tubule cell was injured byCyclosporine, KIM-1expression was increased, in the process of mitogen-activated proteinkinase in the p38pathway, ERK pathway in which play roles. Blocking the p38pathway,blocking the ERK1/2pathway, adding EPO three factors can reduce the renal tubular cellsKIM-1expression, delaying the effective protection and cyclosporine for transplant renaltubular epithelial damage in the process. The results and conclusions of this topic, for thekidney injury molecule-1in renal transplantation field to provide a favorable basis forexperimental evidence, as well as reducing cyclosporine to continue to explore aspects oftransplant renal injury in experimental models and provide reference effective experimentaldrugs.
本选题以KIM-1为研究的核心，探索其在移植肾损伤中的变化和意义。
我们选取2009年-2011年69例移植肾穿刺活检的组织标本，应用免疫组织化学方法标记移植肾组织中KIM-1的表达情况，分析移植肾组织中KIM-1表达水平和其他血液生化指标的关系、移植肾组织中KIM-1表达与移植肾功能的相关性。结果显示：（1）在不同病理诊断分组中可见KIM-1在近端小管上皮出现不同程度的表达；（2）在急性T细胞性排斥反应中，KIM-1表达量随Banff07分级升高而呈现增高趋势，同时KIM-1表达水平与小管炎严重程度相一致。在小管炎出现可见的形态改变之前，KIM-1蛋白已出现可见的阳性表达。（3）慢性活动性抗体介导排异反应中，KIM-1呈强阳性表达，强烈提示活动性排异反应所致肾损伤的存在；（4）在交界性病变时，KIM-1出现不同程度阳性表达，提示肾小管上皮处于损伤状态；（5）未见排斥反应发生和免疫抑制剂中毒组，27.27%（3/11）病例血肌酐在正常范围内，但肾组织中KIM-1呈弱阳性表达。本研究表明：（1）在移植肾组织中KIM-1表达水平与移植肾损伤程度呈正相关，提示肾小管细胞损伤存在。（2）在未见血生化指标升高提示肾损伤时、未见形态学可见肾损伤改变时、未见肾小管炎症反应时，均可见KIM-1蛋白在肾小管上皮细胞表达，提示KIM-1蛋白在移植肾活检组织中表达可以成为早期、敏感、特异判定肾小管上皮细胞损伤的生化指标。
本研究通过采用ELISA方法检测肾移植患者血清中KIM-1的表达，研究和探索早期血清中与组织内KIM-1的表达能否成为早期判断移植肾功能异常的应用指标。结果表明：（1）在移植肾患者血清中KIM-1表达的增强可以提示移植肾损伤程度的强弱。（2）慢性活动性排斥造成的损伤可以出现血清KIM-1的高表达，提示移植肾脏功能状态恶化。（3）早期血清中肾损伤分子-1水平升高可能成为提示移植肾功能状态的生化指标。
在本次实验研究中，采用体外实验方法研究环孢素损伤肾小管细胞后导致其产生KIM-1的表达，并初步探索其中机制，寻找保护和延缓环孢素对移植肾损伤的药物。
在实验中首先建立环孢素损伤肾近曲小管上皮细胞的体外研究模型，采用MTT实验方法筛选环孢素的损伤作用的适宜浓度；采用MTT实验法筛选可能的药物干预改善环孢素对肾小管上皮细胞的损伤；筛选出促红细胞生成素（EPO）可以保护肾小管细胞减少环孢素对细胞的损伤。采用丝裂原活化蛋白激酶系统阻断剂(p38通路阻断剂SB202190、ERK1/2通路阻断剂PD98059)，阻断相应酶的表达，以期推测生化过程发生的机制。采用ELISA方法鉴定KIM-1在细胞上清液中的表达，统计KIM-1表达量的变化。采用流式细胞仪测定在环孢素损伤肾小管中细胞凋亡发生特点。
环孢素使肾近曲小管细胞损伤时KIM-1表达升高并导致细胞凋亡，在这一过程中丝裂原活化蛋白激酶中的p38通路、ERK1/2通路在其中发挥作用。阻断以上2条通路可以减少CsA所致HKC细胞的凋亡比率（P<0.05），增加活细胞比率（P<0.05），减少细胞的坏死比率（P<0.05），同时减少KIM-1蛋白的表达量（P<0.05）。加入EPO可以减少HKC细胞在CsA作用下产生KIM-1蛋白（P<0.05）；选用EPO15U/ml和30U/ml进行实验，随EPO作用量的增加，可以减少HKC细胞在CsA损伤中产生KIM-1的量值，提示EPO可以拮抗CsA对肾小管上皮的损伤，减少CsA所致肾小管上皮细胞凋亡和坏死的发生。
肾损伤分子-1在移植肾中的表达和变化具有重要的研究价值，可以成为判定移植肾损伤早期、敏感、特异性判定肾小管上皮细胞损伤的生化指标；早期血清中肾损伤分子-1水平升高可能成为提示移植肾功能状态的生化指标。环孢素使肾近曲小管细胞损伤时KIM-1表达升高，在这一过程中丝裂原活化蛋白激酶中的p38通路、ERK1/2通路在其中起到作用。阻断p38通路、阻断ERK1/2通路、加入EPO三种因素均可以减少肾小管细胞在CsA作用下产生KIM-1蛋白，有效保护和延缓环孢素对移植肾小管上皮损伤的过程。本次选题的实验结果与结论，为肾损伤分子-1在移植肾领域中的应用提供有利的基础实验依据，同时为减少环孢素对移植肾损伤方面继续探索提供可参考的实验模型与有效的实验药物。
Kidney injury molecule-1(KIM-1) is a new specific biomarker of proximal tubule injurythat can be measured both in urine and kidney tissue samples. It is an apoptotic-cellphagocytosis and scavenger receptor that is most highly upregulated in proximal tubularepithelium in acute and chronic kidney injury. Also, much attention has been paid to itspossible pathophysiological role in modulation of tubular damage and repair. In renalallografts, tubular injury associated with ischemia, nephrotoxicity secondary toimmunosuppressive medication, and/or acute cellular rejection can lead to chronic allograftnephropathy and eventual graft failure. Pre-renal and post-renal factors contributing to renalfailure are not always easily distinguished from intrarenal injury in allograft recipients.Changes in kidney epithelial cell morphology in allograft biopsies can vary from no orminimal histologic changes of proximal tubules to diminished brush borders, apoptosis and/ornecrosis, dilated tubules, and sloughed epithelial cells in the tubular lumina. A pathologicdiagnosis of acute tubular injury is often quite subjective. A sensitive tissue biomarker oftubular injury, which can be used to identify or confirm the presence of epithelial cell injurywhen pathological changes are minimal would be very helpful in the evaluation of biopsyspecimens.
The topic around the KIM-1as the core of the study, we explore the significance of thechange and its expression in the renal allograft injury.
A total of69patients who underwent kidney transplantation between2009-2011wereenrolled in this study. KIM-1expression was detected by immunohistochemical methods andthe association of KIM-1and blood biochemical indexes was analyzed. KIM-1expressionincreased as Banff2007classification grade increased and was positively correlated withtubular inflammation severity in the acute T-cell rejection group. Moreover, KIM-1expression was strongly positive in the chronic active antibodymediated rejection group.Interestingly, KIM-1was weakly positive in the normal group without obvious acute rejection and injury of immunosuppressant toxicity. In this group,27.27%(3/11) of the cases withnormal serum creatinine level showed weakly positive KIM-1expression in their renal tissues.KIM-1expression level is positively correlated with renal allograft damage and tubular cellinjury. KIM-1is expressed in tubular epithelial cells before blood biochemical indexesbecome elevated and morphological changes occur. KIM-1expression is an early, sensitive,and specific biomarker to determine renal tubular epithelial cell injury in renal allograft tissue.
Serum KIM-1expression was detected by ELISA methods, we explore the significanceof the change and its expression in the renal allograft injury.The results showed that:(1) Theserum KIM-1expression is associated with renal allograft injury.(2) Chronic active rejectioncan occur resulting the serum KIM-1expression, suggesting that graft worsening renalfunction status.(3) Early serum kidney injury molecule-1levels may be the new biochemicalmarker for renal allograft function.
In this experimental study, We make use of cyclosporine in renal tubular epithelial injuryin vitro, which produces KIM-1expression and initial exploration of which mechanism tofind drugs which can protect and delay renal allograft injury by cyclosporine.
In the experiment, renal proximal tubule epithelial cells was injuryed by cyclosporine invitro, suitable concentration injury screening of cyclosporine was determined by using the MTTassay method; screening using the MTT assay method of drug intervention may improve renalcyclosporine tubular epithelial cell injury; screened erythropoietin (EPO) can protect renaltubular cells. Using mitogen-activated protein kinase system blockers (p38pathway inhibitorSB202190, ERK1/2pathway inhibitor PD98059), blocking the expression of thecorresponding enzyme mechanisms and biochemical processes occurring to speculate. ELISAusing the method of identifying the expression of KIM-1in the cell supernatant, the KIM-1expression level of statistical variation. Characteristics of the cells was measured by flowcytometry apoptosis in renal tubular injury in cyclosporine
When the renal tubule cell was injured by Cyclosporine, KIM-1expression was increased,in the process of mitogen-activated protein kinase in the p38pathway, ERK1/2pathway playsa role. Blocking these two paths can be reduced HKC CsA-induced apoptosis rate (P <0.05),the ratio of living cells increased (P <0.05), reducing the ratio of necrotic cells (P <0.05), while reducing the KIM-1expression (P <0.05). EPO can be added to reduce the HKC cellsKIM-1protein (P <0.05); optional EPO15U/ml and30U/ml experiment with the effect ofincreasing the amount of EPO may be reduced KIM-1expression, suggesting that EPO mayantagonize CsA on renal epithelial damage, reduce the occurrence of CsA-induced tubularepithelial cell apoptosis and necrosis.
Kidney injury molecule-1expression and changes in renal allograft has importantresearch value, could be early、sensitive、specific determination of renal tubular epithelial cellinjury and biochemical marker for renal allograft injury.The serum kidney injury molecule-1levels may become early biochemical markers. When the renal tubule cell was injured byCyclosporine, KIM-1expression was increased, in the process of mitogen-activated proteinkinase in the p38pathway, ERK pathway in which play roles. Blocking the p38pathway,blocking the ERK1/2pathway, adding EPO three factors can reduce the renal tubular cellsKIM-1expression, delaying the effective protection and cyclosporine for transplant renaltubular epithelial damage in the process. The results and conclusions of this topic, for thekidney injury molecule-1in renal transplantation field to provide a favorable basis forexperimental evidence, as well as reducing cyclosporine to continue to explore aspects oftransplant renal injury in experimental models and provide reference effective experimentaldrugs.
引文
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[44] Chen Z, Gibson TB, Robinson F, et al.MAP kinases [J]. Chem Rev2001;101(8):2449-2476.
[45] Zarubin T, Han J. Activation and signaling of the p38MAP kinase pathway [J]. CellRes2005;15(1):11-18.
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