α-硫辛对糖尿病大鼠肾脏线粒体保护机制的实验研究
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摘要
目的：糖尿病肾病是糖尿病常见的慢性并发症之一,同时也是导致终末期肾病甚至死亡的原因之一。近来研究发现,氧化应激及其诱导的肾脏细胞凋亡在糖尿病肾病发病机制中起重要作用。线粒体不仅是细胞内活性氧簇生成的主要来源,而且是细胞凋亡的控制中心。α-硫辛酸(α-lipoic acid,α-LA)作为一种强抗氧化剂,其对糖尿病肾脏的保护作用得到广泛关注,但其机制尚不明了。本研究探讨高糖诱导的氧化应激状态下大鼠肾脏线粒体功能的变化及其介导的细胞凋亡机制；阐明α-LA对其肾保护作用及相关机制,为α-LA治疗糖尿病肾病提供新的理论依据。
方法：雄性SD大鼠腹腔注射链脲佐菌素(streptozotocin, STZ)诱导糖尿病模型,并将糖尿病模型大鼠随机分为糖尿病非干预组(DM组)和α-LA干预组(α-LA组),以正常大鼠作为对照组(NC组)。干预8周后测定各组大鼠血糖(Blood glucose, BG)、血尿素氮(Blood Urea Nitrogen, BUN)、血肌酐(Serum Creatinine,SCr)及尿白蛋白排泄率(urinary albu min excrection rate, UAER);光镜观察肾脏病理形态学改变,电镜观察肾脏线粒体形态改变；检测血清及肾皮质中丙二醛(malondiadehyde, MDA)的含量及超氧化物岐化酶(superoxide dismutase, SOD)的活性；测定肾脏线粒体呼吸链琥珀酸脱氢酶(succinate dehydrogenase, SDH)及细胞色素C氧化酶的活性；测定肾脏线粒体膜电位及肿胀度变化；免疫组化及Western blotting法检测线粒体电压依赖性阴离子通道(voltage-dependent anion channel,VDAC)蛋白的表达；Western blotting法检测凋亡蛋白细胞色素C(cytochrome C,CytC)表达,免疫组化法检测Smac/DIABLO(the second mitochondria-derived activat or of caspase/direct IAP binding protein)蛋白以及凋亡诱导因子(apoptosis-inducing factor, AIF)的表达。
结果：
1.与NC组相比,DM组BG、BUN、SCr及UAER均明显升高(P<0.01或P<0.05)；a-LA组BUN、SCr及UAER较DM组均明显下降(P<0.01或P<0.05)；DM组和α-LA组的BG水平无统计学差异。
2.光镜显示DM组肾小球体积增大、系膜细胞增多、系膜区细胞外基质增生,电镜显示线粒体出现肿胀,嵴减少。α-LA组上述形态学异常显著改善。
3.与NC组相比,DM组血清及肾皮质MDA水平均显著升高(均P<0.01)；α-LA组较DM组均显著下降(均P<0.05)。与NC组相比,DM组血清及肾皮质SOD活性较NC组均显著下降(均P<0.01),α-LA组较DM组均显著升高(P<0.01或P<0.05)。
4.与NC组相比,DM组肾脏线粒体SDH活性、细胞色素C氧化酶活性、线粒体膜电位均明显降低(P<0.01或P<0.05),线粒体肿胀度趋势明显减弱,电镜显示线粒体出现肿胀,嵴减少。α-LA组肾脏线粒体SDH活性、细胞色素C氧化酶活性、线粒体膜电位较DM组均明显升高(P<0.01或P<0.05),线粒体肿胀度趋势增强。
5.与NC组相比,DM组线粒体蛋白VDAC水平明显降低(P<0.01或P<0.05),凋亡相关蛋白CytC、Smac/DIABLO、AIF表达明显增多(P<0.01或P<0.05)；α-LA组线粒体蛋白VDAC水平明显升高(均P<0.05),凋亡相关蛋白CytC、Smac/DIABLO、AIF表达明显减少(均P<0.05)。
结论：
糖尿病大鼠肾组织中氧化应激水平升高、线粒体功能受损、线粒体VDAC表达降低、线粒体释放的凋亡蛋白CytC、Smac/DIABLO、AIF表达增多肾细胞凋亡启动,参与了DN的发生发展。α-LA通过抑制氧化应激,保护线粒体功能,上调肾脏线粒体VDAC表达抑制线粒体CytC、Smac/DIABLO、AIF的释放阻止肾细胞凋亡的启动,发挥其保护大鼠肾脏的作用。
Objective:
Diabetic nephropathy is one of the common chronic complications of diabetes,which is the one of the leading cause of end-stage renal disease. The recent researches have found that oxidative stress and its mediated apoptosis in kidneys participated the development of diabetic nephropathy. Not only mitochondria constitute the main source of intracellular reactive oxygen series, but also are the central regulator of apoptosis.As a powerful antioxidant, a-lipoic acid(a-LA)plays an important role in renal protection, but the mechanism remains unknown.In this study, we investigate the function changes of mitochondria on kidneys of diabetic rats and renal cell apoptosis mechanism induced by mitochondria, under oxidative stress resulted from high glucose.Meanwhile,we elucidate the protecting effects of a-lipoic acid on kidneys of diabetic rats and explore the related mechanism, which provide new theoretical bases for clinical treatments of diabetic nephropathy.
Methods:
The diabetic model was induced by intraperitoneal injection of streptozotocin(STZ) on Male SD, and then the diabetic rats were randomly divided into two groups:untreated-diabetic group (DM group), a-LA treated-diabetic group(a-LA group), and the normal rats were served as a control group (NC group).At 8 weeks after the onset of diabetes,Blood glucose(BG),Blood Urea Nitrogen(BUN),Serum Creatinine(SCr) and urinary albumin excrection rate (UAER) were detected,histomorphologic changes were observed by optics microscope and morphological changes of mitochondria were observed by electron microscope. The levels of malondiadehyde (MDA) and the activities of superoxide dismutase(SOD), in serum and renal cortex,were also evaluated.Additionally, the activities of succinate dehydrogenase(SDH) and cytochrome C oxidase of renal mitochondrial respiration chain, kidney mitochondrial membrane potential, mitochondrial swelling were measured among the different groups. Apoptosis-related protein cytochrome C (CytC) were tested by Western blotting, while(the second mitochondria-derived activat or of caspase/direct IAP binding protein, Smac/DIABLO)and apoptosis-inducing factor (AIF) were detected by Immunohistochemistry. The expression of (voltage-dependent anion channel,VDAC)on mitochondria was evaluated by both Western blotting and Immunohistochemistry.
Results:
1.Compared with the NC group, BG, BUN, SCr and UAER were significantly increased (P<0.01orP<0.05)in the DM group;BUN,SCr and UAER were significantly decreased in a-LA group compared with the DM group (P＜O.01 or P<0.05);no statistic differences of BG were found between the DM group and the a-LA group.
2.Glomerular hypertrophy, mesangial cell proliferation, extracellular matrix accumulation were observed by optics microscope,the mitochondrial swelling and the diminution of cristae were observed by electron microscopy in the DM group.Abnormal histomorphologic changes described above were obviously improved in the a-LA group.
3.Compared with the NC group,MDA levels were significantly increased in the serum and renal cortex of the DM group(all P<0.01);MDA levels were significantly decreased in the a-LA group compared with the DM group(all P<0.05);Compared with the NC group, the activities of SOD were significantly reduced in the serum and renal cortex of the DM group(all P＜0.01);the activities of SOD were significantly elevated in the a-LA group compared with the DM group(P<0.01 or P<0.05).
4. Compared with the NC group, the activities of SDH, chrome C oxidase, mitochondrial membrane potential were significantly decreased (P＜0.01 or P<0.05);mitochondrial swelling trend remarkably weakened;The activities of SDH,chrome C oxidase, mitochondrial membrane potential in the a-LA group were significantly increased compared with the DM group (P<0.01or P<0.05)and mitochondrial swelling trend reforced.
5.Compared with the NC group, the expression of VDAC on mitochondria were significantly reduced (P＜0.01 or P<0.05),and apoptosis-related protein CytC, Smac/DIABLO,AIF release were significantly elevated in the DM group (P＜0.01 orP<0.05);the expression of VDAC significantly were improved(all P＜0.05),and the expression of apoptosis-related protein CytC, Smac/DIABLO, AIF were significantly reduced in theα-LA group, compared with the DM group(all P<0.05).
Conclusion:
Our findings indicate that oxidative stress,mitochondrial dysfunction, changes in expression of VDAC on mitochondria, CytC,Smac/DIABLO, AIF released by mitochondria may implicate in the mechanism of DN. Moreover, The antioxidant a-LA exert a protective role against the development of DN,the related mechanism may include effectively preventing the generation of oxidants, protecting mitochondrial function, blocking the mitochondrial-dependent apoptosis in renal cells, which is mediated by VDAC via released Cyt C,AIF and Smac/DIABLO.
方法：雄性SD大鼠腹腔注射链脲佐菌素(streptozotocin, STZ)诱导糖尿病模型,并将糖尿病模型大鼠随机分为糖尿病非干预组(DM组)和α-LA干预组(α-LA组),以正常大鼠作为对照组(NC组)。干预8周后测定各组大鼠血糖(Blood glucose, BG)、血尿素氮(Blood Urea Nitrogen, BUN)、血肌酐(Serum Creatinine,SCr)及尿白蛋白排泄率(urinary albu min excrection rate, UAER);光镜观察肾脏病理形态学改变,电镜观察肾脏线粒体形态改变；检测血清及肾皮质中丙二醛(malondiadehyde, MDA)的含量及超氧化物岐化酶(superoxide dismutase, SOD)的活性；测定肾脏线粒体呼吸链琥珀酸脱氢酶(succinate dehydrogenase, SDH)及细胞色素C氧化酶的活性；测定肾脏线粒体膜电位及肿胀度变化；免疫组化及Western blotting法检测线粒体电压依赖性阴离子通道(voltage-dependent anion channel,VDAC)蛋白的表达；Western blotting法检测凋亡蛋白细胞色素C(cytochrome C,CytC)表达,免疫组化法检测Smac/DIABLO(the second mitochondria-derived activat or of caspase/direct IAP binding protein)蛋白以及凋亡诱导因子(apoptosis-inducing factor, AIF)的表达。
结果：
1.与NC组相比,DM组BG、BUN、SCr及UAER均明显升高(P<0.01或P<0.05)；a-LA组BUN、SCr及UAER较DM组均明显下降(P<0.01或P<0.05)；DM组和α-LA组的BG水平无统计学差异。
2.光镜显示DM组肾小球体积增大、系膜细胞增多、系膜区细胞外基质增生,电镜显示线粒体出现肿胀,嵴减少。α-LA组上述形态学异常显著改善。
3.与NC组相比,DM组血清及肾皮质MDA水平均显著升高(均P<0.01)；α-LA组较DM组均显著下降(均P<0.05)。与NC组相比,DM组血清及肾皮质SOD活性较NC组均显著下降(均P<0.01),α-LA组较DM组均显著升高(P<0.01或P<0.05)。
4.与NC组相比,DM组肾脏线粒体SDH活性、细胞色素C氧化酶活性、线粒体膜电位均明显降低(P<0.01或P<0.05),线粒体肿胀度趋势明显减弱,电镜显示线粒体出现肿胀,嵴减少。α-LA组肾脏线粒体SDH活性、细胞色素C氧化酶活性、线粒体膜电位较DM组均明显升高(P<0.01或P<0.05),线粒体肿胀度趋势增强。
5.与NC组相比,DM组线粒体蛋白VDAC水平明显降低(P<0.01或P<0.05),凋亡相关蛋白CytC、Smac/DIABLO、AIF表达明显增多(P<0.01或P<0.05)；α-LA组线粒体蛋白VDAC水平明显升高(均P<0.05),凋亡相关蛋白CytC、Smac/DIABLO、AIF表达明显减少(均P<0.05)。
结论：
糖尿病大鼠肾组织中氧化应激水平升高、线粒体功能受损、线粒体VDAC表达降低、线粒体释放的凋亡蛋白CytC、Smac/DIABLO、AIF表达增多肾细胞凋亡启动,参与了DN的发生发展。α-LA通过抑制氧化应激,保护线粒体功能,上调肾脏线粒体VDAC表达抑制线粒体CytC、Smac/DIABLO、AIF的释放阻止肾细胞凋亡的启动,发挥其保护大鼠肾脏的作用。
Objective:
Diabetic nephropathy is one of the common chronic complications of diabetes,which is the one of the leading cause of end-stage renal disease. The recent researches have found that oxidative stress and its mediated apoptosis in kidneys participated the development of diabetic nephropathy. Not only mitochondria constitute the main source of intracellular reactive oxygen series, but also are the central regulator of apoptosis.As a powerful antioxidant, a-lipoic acid(a-LA)plays an important role in renal protection, but the mechanism remains unknown.In this study, we investigate the function changes of mitochondria on kidneys of diabetic rats and renal cell apoptosis mechanism induced by mitochondria, under oxidative stress resulted from high glucose.Meanwhile,we elucidate the protecting effects of a-lipoic acid on kidneys of diabetic rats and explore the related mechanism, which provide new theoretical bases for clinical treatments of diabetic nephropathy.
Methods:
The diabetic model was induced by intraperitoneal injection of streptozotocin(STZ) on Male SD, and then the diabetic rats were randomly divided into two groups:untreated-diabetic group (DM group), a-LA treated-diabetic group(a-LA group), and the normal rats were served as a control group (NC group).At 8 weeks after the onset of diabetes,Blood glucose(BG),Blood Urea Nitrogen(BUN),Serum Creatinine(SCr) and urinary albumin excrection rate (UAER) were detected,histomorphologic changes were observed by optics microscope and morphological changes of mitochondria were observed by electron microscope. The levels of malondiadehyde (MDA) and the activities of superoxide dismutase(SOD), in serum and renal cortex,were also evaluated.Additionally, the activities of succinate dehydrogenase(SDH) and cytochrome C oxidase of renal mitochondrial respiration chain, kidney mitochondrial membrane potential, mitochondrial swelling were measured among the different groups. Apoptosis-related protein cytochrome C (CytC) were tested by Western blotting, while(the second mitochondria-derived activat or of caspase/direct IAP binding protein, Smac/DIABLO)and apoptosis-inducing factor (AIF) were detected by Immunohistochemistry. The expression of (voltage-dependent anion channel,VDAC)on mitochondria was evaluated by both Western blotting and Immunohistochemistry.
Results:
1.Compared with the NC group, BG, BUN, SCr and UAER were significantly increased (P<0.01orP<0.05)in the DM group;BUN,SCr and UAER were significantly decreased in a-LA group compared with the DM group (P＜O.01 or P<0.05);no statistic differences of BG were found between the DM group and the a-LA group.
2.Glomerular hypertrophy, mesangial cell proliferation, extracellular matrix accumulation were observed by optics microscope,the mitochondrial swelling and the diminution of cristae were observed by electron microscopy in the DM group.Abnormal histomorphologic changes described above were obviously improved in the a-LA group.
3.Compared with the NC group,MDA levels were significantly increased in the serum and renal cortex of the DM group(all P<0.01);MDA levels were significantly decreased in the a-LA group compared with the DM group(all P<0.05);Compared with the NC group, the activities of SOD were significantly reduced in the serum and renal cortex of the DM group(all P＜0.01);the activities of SOD were significantly elevated in the a-LA group compared with the DM group(P<0.01 or P<0.05).
4. Compared with the NC group, the activities of SDH, chrome C oxidase, mitochondrial membrane potential were significantly decreased (P＜0.01 or P<0.05);mitochondrial swelling trend remarkably weakened;The activities of SDH,chrome C oxidase, mitochondrial membrane potential in the a-LA group were significantly increased compared with the DM group (P<0.01or P<0.05)and mitochondrial swelling trend reforced.
5.Compared with the NC group, the expression of VDAC on mitochondria were significantly reduced (P＜0.01 or P<0.05),and apoptosis-related protein CytC, Smac/DIABLO,AIF release were significantly elevated in the DM group (P＜0.01 orP<0.05);the expression of VDAC significantly were improved(all P＜0.05),and the expression of apoptosis-related protein CytC, Smac/DIABLO, AIF were significantly reduced in theα-LA group, compared with the DM group(all P<0.05).
Conclusion:
Our findings indicate that oxidative stress,mitochondrial dysfunction, changes in expression of VDAC on mitochondria, CytC,Smac/DIABLO, AIF released by mitochondria may implicate in the mechanism of DN. Moreover, The antioxidant a-LA exert a protective role against the development of DN,the related mechanism may include effectively preventing the generation of oxidants, protecting mitochondrial function, blocking the mitochondrial-dependent apoptosis in renal cells, which is mediated by VDAC via released Cyt C,AIF and Smac/DIABLO.
引文
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1.Ceriell o A, Mercuri F, Quagliaro L, et al.Detection of nitrotyrosine in the diabetic plasma:evidence of oxidative stress[J].Diabetologia,2001,44(7):834-838
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4.Xu G W, Yao QH,Weng QF, et al.Study of urinary 8-hydroxy deox-yguanosine as a biomarker of oxidative DNA damage in diabetic nephropathy patients [J].J Pharm Bi omed Anal,2004,36(1):101-104.
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6.Brownlee M.Preventing kidney cell suicide [J].Nat Med,2007,13:1284-1285.
7.Houten BV, Woshner V, Santos JH.Role of mitochondrial DNA in toxic responses to oxidative stress[J].DNA Repair(Amst),2006,5(2):145-152.
8.Wiseman, A. p53 Protein or BID protein select the route to either apoptosis (programmed cell death) or to cell cycle arrest opposing carcinogenesis after DNA damage by ROS. Medical Hypotheses,2006,67:296-299.
9.Ka, H.,Park, H.-J.,Jung, etal.Cinnamaldehyde induces apoptosis by ROS-mediated mitochondrial permeability transition in human promyelocytic leukemia HL-60 cells.Cancer Letters,2003,196:143-152.
1O.Liu BF, Miyata S,Hirota Y, etal. Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells[J].Kidney International, 2003,63(3):947-957.
11.Petermann AT, Krofft R, Blonski M, etal.Podocytes that detach in experimental membranous nephropathy are viable[J].Kidney Int,2003,64:1222-1231.
12.Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy[J]. Diabetes,2006,55(1):225-233.
13.Kelly DJ, CoxAJ, TolcosM, et al.Attenuation of tubular apoptosis by blockade of the rennin-angiotensin system in diabetic Ren rats[J].Kidney Int,2002,61(1):31-39.
14.Bras M, Queenan B,Susin SA. Programmed cell death via mitochondria:different modes of dying[J].Biochemistry (Mosc),2005,(70):231-239
15.Kroemer, G, Reed JC.Mitochondrial control of cell death. Nat[J].Med,2000,6(5): 513-519.
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17.Pradelli L A, Beneteau M. Ricc JE.Mitochondrial control of caspase-dependent and-independent cell death. Cell Mol Life Sci,2010,67(10):1589-97.
18.Michael R Duchen.Mitochondria in health and disease perspectives on a new mitochondrial biology[J].Molecular Aspects of Medicine,2004,25(4):365-4511.
19.安冉,董强.凋亡过程中线粒体膜透化的常用检测方法[J].中华脑血管病杂志(电子版),2009,3(1)：33-37
20.Wang, XD. The expanding role of mitochondria in apoptosis[J].Genes & Development,2001,(15) 2922-2933.
21.Gross A, Mc Donnell JM, Korsmeyer SJ.BCL-2 family members and the mitochondria in apoptosis[J].Genes Dev,1999(13)1899-1911.
22.Frenzel A, Grespi F, Chmelewskij WA etal.Bcl-2 family proteins in carcinogenesis and the treatment of cancer[J].Apoptosis,2009,14(4):584-596
23.Adrain C, Creagh EM, Martin SJ etal.Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2[J].EMBO J, 2001,20 6627-6636.
24. Kang BPS, Urbonas A, Baddoo A et al.IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose[J].Am J Physiol Renal Physiol, 2003,285:1013-1024.
25.Kang BPS, Frencher S, Reddy V et al.High glucose promotes mesangial cell apoptosis by oxidant-dependent mechanism[J].Am J Physiol Renal Physiol,2003, 284:455～466.
26.Verzola D, Bertolotto MB, Villaggio B et al.Taurine prevents apoptosis induced by high ambient glucose in human tubule renal cells[J].J Investig Med,2002,50: 443～451.
27.Allen DA, Harwood SM, Varagunam M et al. High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases[J].2003,FASEB J 17:908.