辛伐他汀诱导血红素加氧酶-1高表达减轻肾脏缺血再灌注损伤的作用研究
摘要
目的：
采用辛伐他汀干预缺血再灌注损伤(IRI)大鼠,检测肾组织中血红素加氧酶-1(heme oxygenase-1, HO-1)的表达水平,探讨他汀类药物在肾IRI中的保护作用及可能机制。
方法：
采用切除大鼠右肾,夹闭左肾蒂45分钟再灌注24小时,建立缺血再灌注损伤模型。健康雄性Wistar大鼠40只随机分为4组,即辛伐他汀组(statin组,n=10)、缺血再灌注组(IR组,n=10)、血红素加氧酶-1抑制剂组(ZnPP组,n=10)和假手术组(sham组,n=10)。statin组辛伐他汀10mg／kg／d术前灌胃7天,IR组等体积生理盐水术前灌胃7天,ZnPP组锌原卟啉术前24小时5mg／kg腹腔注射,sham组正常喂养。前三组建立IRI模型,sham组仅切除右肾。24小时后测定各组大鼠血尿素氮(BUN)、肌酐(Cr)含量,同时行HE染色观察肾脏病理形态学改变,并对肾小管损伤情况进行评分,另外采用免疫组织化学染色法检测血红素加氧酶-1在肾脏的表达和分布情况。
结果：
1各组大鼠肾功能改变
与sham组相比,IR组、statin组及ZnPP组大鼠都有不同程度的肾功能损害,表现为BUN和Cr值不同程度的增高(P<0.01),三组中statin组肾功能受损最轻,ZnPP组肾功能损伤最重。与IR组相比,statin组BUN、Cr值明显降低,两组间差异有统计学意义(P<0.01)。IR组肾功能损伤轻于ZnPP组,两组间差异亦有统计学意义(P<0.01)。
2肾脏组织形态学改变
光镜下观察见IR组肾小管上皮细胞明显水肿样变性,肾小管的刷状缘脱落或部分脱落,管腔扩张,以远曲小管和集合管为重,并见管型,肾间质局部出血伴水肿,可见炎性细胞浸润；statin组仅见部分肾小管上皮细胞轻度水肿样变性,偶见管型及炎性细胞浸润；ZnPP组损伤最重,肾小管结构破坏,大量管型形成,肾间质炎性细胞浸润；sham组肾小球和小管形态正常,间质无水肿及炎性细胞浸润。各组中肾小球均无明显变化。
3肾小管评分
与sham组相比,ZnPP组肾小管评分(239.70±4.79,P<0.05)最高,损伤最重,单纯IR组其次(104.38±5.57,P<0.05),statin组明显低于前两者(39.51±1.62,P<0.05)。sham组评分最低,损伤最轻。
4 HO-1在肾组织的表达及分布状况的免疫组化分析
statin组和IR组均有HO-1的表达,主要表达于近曲小管、远曲小管上皮细胞,髓袢小管和集合管上皮细胞,阳性细胞多分布在皮质近髓部和髓质部,并存在皮髓质梯度。statin组HO-1表达水平最高,呈强阳性。IR组次之,呈弱阳性表达。假手术组仅有少量HO-1表达,而HO-1的抑制剂ZnPP组几乎不表达HO-1。
结论：
在肾脏缺血再灌注中,HO-1是一种重要的细胞保护因子,辛伐他汀能减轻肾脏缺血再灌注损伤,其机制可能与诱导HO-1高表达有关。
Objective:To investigate the expression levels and the roles of heme oxygenase-1 (HO-1) induced by simvastatin in rat kidneys through the ischemia-reperfusion injury(IRI) model and explore the possible protective mechanism of simvastatin on kidneys.
Methods:In brief, for IR injury the left renal pedicle was occluded for 45 minutes, and the contralateral right kidney was removed.40 male healthy Wistar rats were randomized into four experimental groups of 10 animals each:simvastatin group, IR group, HO-1 inhibitor group and sham group. For sham group, the right kidneys were excised merely.24 hours after surgery, blood samples were drawn for measurement of serum urea nitrogen (BUN) and creatinine (Cr) concentrations by an automated method. Moreover, pathologic changes of the kidney was observed under light microscopy by HE stain to evaluate the injuries of renal tubules and the expression levels of HO-1 in rat kidneys were measured by immunohistochemistry meanwhile.
Results:
1. The comparisons of renal functions among different groups
Compared with sham group, the serum levels of BUN and Cr in other groups were significantly higher than those in sham group (P<0.01), and ZnPP group was the highest, while statin group was the lowest. When comparing with IR group, the BUN and Cr were obviously lower in the statin group (P<0.01), however, the injury of renal functions of IR group was much better than those in ZnPP group (P<0.01).
2. The histomorphologic changes of rat kidneys
The renal tubular epithelial cells of IR group became edematous with their brush borders falling off partly or completely. Some renal tubule lumens were dilated, while some of them were filled with casts. All these changes were extremely obvious in distal tubules and collecting tubules. Meanwhile, renal interstitium was infiltrated with inflammatory cells with local bleeding and edema. According to the statin group, the pathological changes were much slighter with lesser casts and inflammatory cells. Among all groups, the injury in ZnPP group was the most severe, whose renal tubules were absolutely destroyed. Conversely, the morphologic changes of kidneys in sham group were almost similar to normal kidneys without edema or inflammation. The renal glomeruli were normal in all groups.
3. The pathologic Paller's grades of renal tubules
The more grades of renal tubules, the more severe of the injuries would be. Compared with sham group, the grades of ZnPP group was the highest (239.70±4.79, P<0.05) and IR group was the second (104.38±5.57, P<0.05), while statin group was lower than both of them (39.51±1.62, both P<0.05). The grades of the sham group was the least, which means the injury was the slightest.
4. The expressions and distributions of HO-1 in kidneys
The expressions of HO-1 could be found both in statin group and IR group, which mainly distributed in the epithelial cells of proximal and distal tubules, henle loops and collecting tubules. Moreover, the expression levels of HO-1 were diverse in different locations, the colser to the medulla, the more HO-1 would be. Among all groups, HO-1 was the most in the statin group, and IR group was the second. On the contrary, there was almost no HO-1 in ZnPP group, and little HO-1 was found in sham group.
Conclusion:
HO-1 was a significant cell protective factor for renal ischemia-reperfusion injury, and simvastatin may attenuates renal ischemia-reperfusion injuries by up-regulating the expression levels of HO-1.
采用辛伐他汀干预缺血再灌注损伤(IRI)大鼠,检测肾组织中血红素加氧酶-1(heme oxygenase-1, HO-1)的表达水平,探讨他汀类药物在肾IRI中的保护作用及可能机制。
方法：
采用切除大鼠右肾,夹闭左肾蒂45分钟再灌注24小时,建立缺血再灌注损伤模型。健康雄性Wistar大鼠40只随机分为4组,即辛伐他汀组(statin组,n=10)、缺血再灌注组(IR组,n=10)、血红素加氧酶-1抑制剂组(ZnPP组,n=10)和假手术组(sham组,n=10)。statin组辛伐他汀10mg／kg／d术前灌胃7天,IR组等体积生理盐水术前灌胃7天,ZnPP组锌原卟啉术前24小时5mg／kg腹腔注射,sham组正常喂养。前三组建立IRI模型,sham组仅切除右肾。24小时后测定各组大鼠血尿素氮(BUN)、肌酐(Cr)含量,同时行HE染色观察肾脏病理形态学改变,并对肾小管损伤情况进行评分,另外采用免疫组织化学染色法检测血红素加氧酶-1在肾脏的表达和分布情况。
结果：
1各组大鼠肾功能改变
与sham组相比,IR组、statin组及ZnPP组大鼠都有不同程度的肾功能损害,表现为BUN和Cr值不同程度的增高(P<0.01),三组中statin组肾功能受损最轻,ZnPP组肾功能损伤最重。与IR组相比,statin组BUN、Cr值明显降低,两组间差异有统计学意义(P<0.01)。IR组肾功能损伤轻于ZnPP组,两组间差异亦有统计学意义(P<0.01)。
2肾脏组织形态学改变
光镜下观察见IR组肾小管上皮细胞明显水肿样变性,肾小管的刷状缘脱落或部分脱落,管腔扩张,以远曲小管和集合管为重,并见管型,肾间质局部出血伴水肿,可见炎性细胞浸润；statin组仅见部分肾小管上皮细胞轻度水肿样变性,偶见管型及炎性细胞浸润；ZnPP组损伤最重,肾小管结构破坏,大量管型形成,肾间质炎性细胞浸润；sham组肾小球和小管形态正常,间质无水肿及炎性细胞浸润。各组中肾小球均无明显变化。
3肾小管评分
与sham组相比,ZnPP组肾小管评分(239.70±4.79,P<0.05)最高,损伤最重,单纯IR组其次(104.38±5.57,P<0.05),statin组明显低于前两者(39.51±1.62,P<0.05)。sham组评分最低,损伤最轻。
4 HO-1在肾组织的表达及分布状况的免疫组化分析
statin组和IR组均有HO-1的表达,主要表达于近曲小管、远曲小管上皮细胞,髓袢小管和集合管上皮细胞,阳性细胞多分布在皮质近髓部和髓质部,并存在皮髓质梯度。statin组HO-1表达水平最高,呈强阳性。IR组次之,呈弱阳性表达。假手术组仅有少量HO-1表达,而HO-1的抑制剂ZnPP组几乎不表达HO-1。
结论：
在肾脏缺血再灌注中,HO-1是一种重要的细胞保护因子,辛伐他汀能减轻肾脏缺血再灌注损伤,其机制可能与诱导HO-1高表达有关。
Objective:To investigate the expression levels and the roles of heme oxygenase-1 (HO-1) induced by simvastatin in rat kidneys through the ischemia-reperfusion injury(IRI) model and explore the possible protective mechanism of simvastatin on kidneys.
Methods:In brief, for IR injury the left renal pedicle was occluded for 45 minutes, and the contralateral right kidney was removed.40 male healthy Wistar rats were randomized into four experimental groups of 10 animals each:simvastatin group, IR group, HO-1 inhibitor group and sham group. For sham group, the right kidneys were excised merely.24 hours after surgery, blood samples were drawn for measurement of serum urea nitrogen (BUN) and creatinine (Cr) concentrations by an automated method. Moreover, pathologic changes of the kidney was observed under light microscopy by HE stain to evaluate the injuries of renal tubules and the expression levels of HO-1 in rat kidneys were measured by immunohistochemistry meanwhile.
Results:
1. The comparisons of renal functions among different groups
Compared with sham group, the serum levels of BUN and Cr in other groups were significantly higher than those in sham group (P<0.01), and ZnPP group was the highest, while statin group was the lowest. When comparing with IR group, the BUN and Cr were obviously lower in the statin group (P<0.01), however, the injury of renal functions of IR group was much better than those in ZnPP group (P<0.01).
2. The histomorphologic changes of rat kidneys
The renal tubular epithelial cells of IR group became edematous with their brush borders falling off partly or completely. Some renal tubule lumens were dilated, while some of them were filled with casts. All these changes were extremely obvious in distal tubules and collecting tubules. Meanwhile, renal interstitium was infiltrated with inflammatory cells with local bleeding and edema. According to the statin group, the pathological changes were much slighter with lesser casts and inflammatory cells. Among all groups, the injury in ZnPP group was the most severe, whose renal tubules were absolutely destroyed. Conversely, the morphologic changes of kidneys in sham group were almost similar to normal kidneys without edema or inflammation. The renal glomeruli were normal in all groups.
3. The pathologic Paller's grades of renal tubules
The more grades of renal tubules, the more severe of the injuries would be. Compared with sham group, the grades of ZnPP group was the highest (239.70±4.79, P<0.05) and IR group was the second (104.38±5.57, P<0.05), while statin group was lower than both of them (39.51±1.62, both P<0.05). The grades of the sham group was the least, which means the injury was the slightest.
4. The expressions and distributions of HO-1 in kidneys
The expressions of HO-1 could be found both in statin group and IR group, which mainly distributed in the epithelial cells of proximal and distal tubules, henle loops and collecting tubules. Moreover, the expression levels of HO-1 were diverse in different locations, the colser to the medulla, the more HO-1 would be. Among all groups, HO-1 was the most in the statin group, and IR group was the second. On the contrary, there was almost no HO-1 in ZnPP group, and little HO-1 was found in sham group.
Conclusion:
HO-1 was a significant cell protective factor for renal ischemia-reperfusion injury, and simvastatin may attenuates renal ischemia-reperfusion injuries by up-regulating the expression levels of HO-1.
引文
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[14]刘秉乾,武玉东,马腾骧.血红素氧合酶-1对大鼠肾缺血再灌注损伤的保护作用[J].中华实验外科杂志,2004,21(12)：1531-1532.
[15]Leung N, Croatt AJ, Haggard JJ, et al. Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat[J]. Kidney Int,2001,60(3):1047-1057.
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[22]Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice[J]. Nat Med,2002,8(3):240-246.
[23]Otterbein LE, Choi AM. Heme oxygenase:colors of defense against cellular stress[J]. Am J Physiol lung Cell Mol Physiol,2000,279(6):L1029-1037.
[24]Nath KA. Heme oxygenase-1:A provenance for cytoprotective pathways in the kidney and other tissues[J]. Kidney Int,2006,70(3):432-443.
[25]Takeda Y, TakenoM, IwasakiM, et al. Chemical induction of HO-1 suppresses lupus nephritis by reducing local iNOS expression and synthesis of anti-dsDNA antibody [J]. Clin Exp Immuno,2004,138(2):237-244.
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