rhKD/APP对大鼠肾缺血再灌注损伤的保护作用及机制的研究
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摘要
研究背景：对Kunitz型蛋白酶抑制剂BPTI与人源型Kunitz型蛋白酶抑制剂rhKD／APP及肾缺血再灌注损伤的发病机制和治疗战略研究进展进行了综述。目前国内外将BPTI应用于肾保护的报导甚少，尚未见rhKD／APP应用于肾保护的报导。
本研究对经过基因重组技术筛选出的稳定高效的工程菌株rhKD／APP在肾缺血再灌注损伤的器官保护药效学方面进行了多角度的研究。我们通过大鼠肾蒂夹闭建立缺血再灌注(I／R)模型，观察rhKD／APP的干预治疗对缺血再灌注肾功能及超微结构的改变，通过临床和病理两方面研究rhKD／APP是否对肾缺血再灌注具有保护作用，同时从自由基-抗自由基平衡、炎性网络平衡以及细胞凋亡-抗凋亡平衡这三个最重要的肾缺血再灌注损伤机制，探讨rhKD／APP具有肾脏保护作用的可能机制。
结果表明rhKD／APP干预组大鼠血肌酐、尿素氮及尿NAG水平较对照组相比升高程度明显为轻，在肾脏超微结构方面rhKD／APP组的肾脏组织结构破坏明显轻于对照组。提示rhKD／APP对肾缺血再灌注损伤具有一定的保护作用。在rhKD／APP肾脏保护机制的研究中发现rhKD／APP组血清MDA、NO含量及活性明显下调，SOD、GSH-PX活性明显上调，提示rhKD／APP在大鼠肾缺血再灌注时发挥了自由基清除作用；rhKD／APP组血清MPO含量、TNF-a、NF-KB浓度明显低于对照组，提示rhKD／APP抑制或减轻了炎症级联放大效应；rhKD／APP组肾脏TUNEL阳性反应细胞数明显减少，凋亡指数显著减少，提示rhKD／APP能够通过抗凋亡作用发挥肾保护作用。
本实验的创新之处在于：
1)将Kunitz型蛋白酶抑制剂应用于肾缺血再灌注损伤的干预治疗，国内外尚未见报道。
2)证实了rhKD／APP对肾缺血再灌注损伤大鼠具有保护作用，并认为其机制可能是通过清除自由基、抑制炎症级联放大反应、延迟细胞凋亡等多层面发挥肾脏保护作用，国内外尚未见报道。
Renal ischemia-reperfusion injury is that the function of kidney tissue can not return to normal during the ischemia and after reperfusion, even the more serious tissue injury or organ function failure. The mechanism of acute ischemia-reperfusion injury is not clear, but the recent findings show that it relates to the production of radical, over-load of intracellular calcium, neutrophil, IL-8, apopotosis-gene regulatory, the detachment and attachment of renal tubular cells, the injury of renal tubular and glomerular cells mediated by NO, ET.
This article reviews the protective effects and mechanism of human Kunitz protease inhibitor rhKD/APP on renal ischemia-reperfusion injury.
From the aspect of the pharmacodynamics of organ-protection after renal ischemia-reperfusion injury, we make a multi-angle research of stability and high expression strain rhKD/APP screened by genetic combination technique. We established the ischemia-reperfusion model by knotting the kidney artery, and then observed the changes of renal function and kidney morphological structure after the treatment of ischemia-reperfusion injury by intervention of rhKD/APP. From the clinical and pathological aspects, we observed whether rhKD/APP has the protective effects on the renal ischemia-reperfusion injury and discussed the probable kidney protective mechanism of rhKD/APP based on three biggest network of renal ischemia-reperfusion mechanism the balance between the radical and anti-radical, the balance of inflammatory network, the balance between the cell apoptosis and anti-apoptosis.
The results showed that rhKD/APP treatment group, compared with the sham group, had a less lift of SCr and BUN, and the tissue destruction was lighter than the latter in the aspect of morphological structure, it suggests that rhKD/APP has the protective effects on renal ischemia-reperfusion injury. During the research of the mechanism of kidney protection, we found that the content of MDA, NO and the activity of NAG in the rhKD/APP group decreased significantly, while the activity of SOD and GSH-PX increased significantly, it suggests that rhKD/APP played its role in radical scavenging in the renal ischemia-reperfusion; compared with the blank group, the content of serum MPO, TNF-a、NF-rB decreased significantly, it suggests that rhKD/APP can promote the inflammatory network balance; The TUNEL positive kidney cell of rhKD/APP group decreased significantly, and the extent of DNA breakage reduced significantly, it suggests that rhKD/APP exerts its function of kidney protection by anti-apoptosis effects.
In conclusion, human Kunitz protease inhibitor rhKD/APP exerts the protective effects on renal ischemia-reperfusion injury by scavenging the radical, inhibiting the inflammatory mediators and anti-apoptosis effect.
本研究对经过基因重组技术筛选出的稳定高效的工程菌株rhKD／APP在肾缺血再灌注损伤的器官保护药效学方面进行了多角度的研究。我们通过大鼠肾蒂夹闭建立缺血再灌注(I／R)模型，观察rhKD／APP的干预治疗对缺血再灌注肾功能及超微结构的改变，通过临床和病理两方面研究rhKD／APP是否对肾缺血再灌注具有保护作用，同时从自由基-抗自由基平衡、炎性网络平衡以及细胞凋亡-抗凋亡平衡这三个最重要的肾缺血再灌注损伤机制，探讨rhKD／APP具有肾脏保护作用的可能机制。
结果表明rhKD／APP干预组大鼠血肌酐、尿素氮及尿NAG水平较对照组相比升高程度明显为轻，在肾脏超微结构方面rhKD／APP组的肾脏组织结构破坏明显轻于对照组。提示rhKD／APP对肾缺血再灌注损伤具有一定的保护作用。在rhKD／APP肾脏保护机制的研究中发现rhKD／APP组血清MDA、NO含量及活性明显下调，SOD、GSH-PX活性明显上调，提示rhKD／APP在大鼠肾缺血再灌注时发挥了自由基清除作用；rhKD／APP组血清MPO含量、TNF-a、NF-KB浓度明显低于对照组，提示rhKD／APP抑制或减轻了炎症级联放大效应；rhKD／APP组肾脏TUNEL阳性反应细胞数明显减少，凋亡指数显著减少，提示rhKD／APP能够通过抗凋亡作用发挥肾保护作用。
本实验的创新之处在于：
1)将Kunitz型蛋白酶抑制剂应用于肾缺血再灌注损伤的干预治疗，国内外尚未见报道。
2)证实了rhKD／APP对肾缺血再灌注损伤大鼠具有保护作用，并认为其机制可能是通过清除自由基、抑制炎症级联放大反应、延迟细胞凋亡等多层面发挥肾脏保护作用，国内外尚未见报道。
Renal ischemia-reperfusion injury is that the function of kidney tissue can not return to normal during the ischemia and after reperfusion, even the more serious tissue injury or organ function failure. The mechanism of acute ischemia-reperfusion injury is not clear, but the recent findings show that it relates to the production of radical, over-load of intracellular calcium, neutrophil, IL-8, apopotosis-gene regulatory, the detachment and attachment of renal tubular cells, the injury of renal tubular and glomerular cells mediated by NO, ET.
This article reviews the protective effects and mechanism of human Kunitz protease inhibitor rhKD/APP on renal ischemia-reperfusion injury.
From the aspect of the pharmacodynamics of organ-protection after renal ischemia-reperfusion injury, we make a multi-angle research of stability and high expression strain rhKD/APP screened by genetic combination technique. We established the ischemia-reperfusion model by knotting the kidney artery, and then observed the changes of renal function and kidney morphological structure after the treatment of ischemia-reperfusion injury by intervention of rhKD/APP. From the clinical and pathological aspects, we observed whether rhKD/APP has the protective effects on the renal ischemia-reperfusion injury and discussed the probable kidney protective mechanism of rhKD/APP based on three biggest network of renal ischemia-reperfusion mechanism the balance between the radical and anti-radical, the balance of inflammatory network, the balance between the cell apoptosis and anti-apoptosis.
The results showed that rhKD/APP treatment group, compared with the sham group, had a less lift of SCr and BUN, and the tissue destruction was lighter than the latter in the aspect of morphological structure, it suggests that rhKD/APP has the protective effects on renal ischemia-reperfusion injury. During the research of the mechanism of kidney protection, we found that the content of MDA, NO and the activity of NAG in the rhKD/APP group decreased significantly, while the activity of SOD and GSH-PX increased significantly, it suggests that rhKD/APP played its role in radical scavenging in the renal ischemia-reperfusion; compared with the blank group, the content of serum MPO, TNF-a、NF-rB decreased significantly, it suggests that rhKD/APP can promote the inflammatory network balance; The TUNEL positive kidney cell of rhKD/APP group decreased significantly, and the extent of DNA breakage reduced significantly, it suggests that rhKD/APP exerts its function of kidney protection by anti-apoptosis effects.
In conclusion, human Kunitz protease inhibitor rhKD/APP exerts the protective effects on renal ischemia-reperfusion injury by scavenging the radical, inhibiting the inflammatory mediators and anti-apoptosis effect.
引文
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