肾衰养真胶囊对5/6肾切除大鼠的调脂作用及LPL基因表达的影响
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摘要
背景及目的：脂代谢紊乱(Dyslipidemia)是CRF常见代谢紊乱之一，可由各种原因引起，脂蛋白脂酶(lipoprotein lipase，LPL)作为脂质分解代谢的关键脂酶，在CRF脂代谢中起着极其重要的作用。脂代谢紊乱不仅导致CRF病人心血管系统疾病危险性增加，而且加速肾小球硬化。调脂治疗对于延缓CRF进展显得尤为重要。本研究旨在观察肾衰养真胶囊(SSYZ)对5／6肾切除大鼠的调脂及肾保护作用和对心肌脂蛋白脂酶(LPL)基因表达的影响，探讨SSYZ的作用机制。
方法：1．采用5／6肾切除法制造大鼠CRF模型，设立正常对照组(Nc组)、模型对照组(CC组)、吉非罗齐治疗组(C+G组)、肾衰养真胶囊高剂量治疗组(C+HSSYZ组)、肾衰养真胶囊中剂量治疗组(C+MSSYZ组)、肾衰养真胶囊低剂量治疗组(C+LSSYZ组)，治疗4周。观察治疗期间及治疗后大鼠一般状况(精神状态、食欲、毛色、体重等)，测定白蛋白(ALB)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLc)、极低密度脂蛋白胆固醇(VLDLc)、高密度脂蛋白胆固醇(HDLc)。
2．测定各组大鼠血清尿素氮(BUN)、血肌酐(SCr)及取上述各组动物肾脏进一步作肾脏病理检测。用光镜法观察大鼠肾脏病理。
3．取上述各组动物心脏进一步研究心肌LPL活性及LPL基因表达。用紫外分光光度法测定大鼠心肌LPL活性，用半定量反转录聚合酶链式反应(RT-PCR)法检测其心肌LPLmRNA的表达。
结果：1．模型对照组(CC组)出现白蛋白、HDLc下降，胆固醇、甘油三酯，LDLc，VLDLc持续升高。治疗四组(C+G、C+HSSYZ、C+MSSYZ、C+LSSYZ)白蛋白、HDLc也下降，也出现胆固醇、甘油三
醋，LDLc，vLDL。升高，但治疗后，可以改善大鼠一般状况，降低胆
固醇、甘油三醋，LDL。，升高HDLc。SsYZ治疗组作用与吉非罗齐作
用相似，SSYZ各治疗组之间无剂量依赖关系，且能够显著提高白蛋白。
2.CC组出现尿素氮、肌配上升，病理检查出现较严重的肾小球及小
管l’ed质病变。治疗四组(e+o、e+Hss犯、e+MssYZ、C+LSsYZ)尿
素氮、肌配也持续上升，也出现肾功能下降，肾病理损害，但治疗后，
可以降低尿素氮、肌配，对肾脏形态学损害有一定保护作用。Ssyz治
疗三组降尿素氮、肌配作用较吉非罗齐组比较有显著差异(P<0 .01)。
3.对心肌LPL活性及LPL基因表达研究结果表明:CC组心肌LPL
活性浓度及LPLmRNA相对含量较NC组显著下降(P<0.01);治疗四组
(C+G、C十HSSYZ、C+MSSYZ、C+LSSYZ)心肌LPL活性浓度均比
CC组有显著升高，治疗各组之间无显著差异。治疗四组对LPLmRNA表达
显著上调，与CC组相比有显著差异(P<0.01)，治疗各组之间无显著差
异(P> .05)。
结论:SSYZ、吉非罗齐显著调节C盯大鼠血脂水平，SSYZ各治疗
组之间无量效依赖关系。这一改善脂代谢紊乱的作用可能部份是通过提
高LPL活性及LPLmRNA表达上调而实现。SSYZ作用与吉非罗齐作用
相似，在提高白蛋白、改善肾功能及肾脏病理形态损伤的治疗作用较吉
非罗齐好。
Background and Objective: Dyslipidemia occurred in the majority of patients with chronic renal failure. The cause of dyslipidemia is multifactorial. Reduced lipoprotein lipase (LPL) activity played a key role. Dyslipidemia not only leaded patients with renal disease to belonging to a very high cardiovascular risk group but also aggravated renal sclerosis. Dyslipidemia should most likely be subjected to sufficient lipid-lowering therapy in preventing nephropathy process. The purpose of the study was to investigate the therapeutic effect of capsule of shen-shuai-yang-zhen(SSYZ) on lipid metabolism disorder and renal function in rats with 5/6 nephrectomy, Simultaneously, evaluate the cordis Lipoprotein Lipase gene expression, trying to find the therapeutic mechanism of the SSYZ to the CRF rats.
Methods: 1. SD rats were made into CRF model by 5/6 nephrectomy. Rats were randomly sorted into the following groups. Normal control group(NC), CRF control group(CC), Gemfrozil group(C+G), High dose ssyz group(C+HSSYZ), Moderate dose ssyz group(C+MSSYZ), Low dose ssyz group(C+LSSYZ). All rats were treated with corresponding drugs for 4 weeks. During and after the treatment, the general state, serum albumin(AL B), total cholesterol(TC), triglyceride(TG), low density lipoprotein cholest er-ol(LDLc), very low density lipoprotein cholesterol(VLDLc) and high density lipoprotein cholesterol(HDLc) were detected.
2. Blood urea nitrogen contents(BUN) and serum creatinine(SCr) were detected. The kidenys of the rats were used for the study of nephron pathology. Kidney pathological features were observed under microscope.
3. The myocaridum of the rats were used for the study of lipoprotein lipase activity and lipoprotein lipase gene expression, lipoprotein lipase activity was assayed using ultraviolet spectrophotometer, lipoprotein lipase messenger RNA (LPLmRNA) levels were detected by semi-quantitative RT-PCR. blood lipid parameters in CRF rats were detected.
Results: 1. Dyslipidemia occurred in the five CRF groups. SSYZ and Gemfibrozil could improve the general state, HDLc. Besides, TC, TG and LDLc concentrations were decreased (P<0.01) . There were no differentiae among SSYZ and Gemfibrozil groups. There were no dose depend effects in SSYZ groups which can increase serum ALB.
2. Blood urea nitrogen contents(BUN) level, serum creatinine(SCr) level and renal lesions were occured in CC group. SSYZ had better effect on decreasing blood urea nitrogen contents(BUN) level, serum creatinine(SCr) level and on improving renal lesions than Gemfibrozil.
3. The study on the LPL gene expression in heart shows: the LPL gene expression and the LPL activity of CRF rats were significantly upregulated, SSYZ and Gemfibrozil could upregulate the LPL gene expression and the LPL activity. There were no differentiae between SSYZ and Gemfibrozil groups.
Conclusion: The results of the present study provide some evidences that SSYZ and Gemfibrozil can obviously regulate lipids level and improve it in renal insufficiency rats by enhance LPL activity and LPL gene expression. This effect maybe one of the mechanisms that SSYZ adjusts abnormity of lipids of chronic renal failure (CRF) rats. There were no differentia between SSYZ and Gemfibrozil groups. But SSYZ has a better certain effect on preventing nephropathy process, and raising the serum level of ALB.
方法：1．采用5／6肾切除法制造大鼠CRF模型，设立正常对照组(Nc组)、模型对照组(CC组)、吉非罗齐治疗组(C+G组)、肾衰养真胶囊高剂量治疗组(C+HSSYZ组)、肾衰养真胶囊中剂量治疗组(C+MSSYZ组)、肾衰养真胶囊低剂量治疗组(C+LSSYZ组)，治疗4周。观察治疗期间及治疗后大鼠一般状况(精神状态、食欲、毛色、体重等)，测定白蛋白(ALB)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLc)、极低密度脂蛋白胆固醇(VLDLc)、高密度脂蛋白胆固醇(HDLc)。
2．测定各组大鼠血清尿素氮(BUN)、血肌酐(SCr)及取上述各组动物肾脏进一步作肾脏病理检测。用光镜法观察大鼠肾脏病理。
3．取上述各组动物心脏进一步研究心肌LPL活性及LPL基因表达。用紫外分光光度法测定大鼠心肌LPL活性，用半定量反转录聚合酶链式反应(RT-PCR)法检测其心肌LPLmRNA的表达。
结果：1．模型对照组(CC组)出现白蛋白、HDLc下降，胆固醇、甘油三酯，LDLc，VLDLc持续升高。治疗四组(C+G、C+HSSYZ、C+MSSYZ、C+LSSYZ)白蛋白、HDLc也下降，也出现胆固醇、甘油三
醋，LDLc，vLDL。升高，但治疗后，可以改善大鼠一般状况，降低胆
固醇、甘油三醋，LDL。，升高HDLc。SsYZ治疗组作用与吉非罗齐作
用相似，SSYZ各治疗组之间无剂量依赖关系，且能够显著提高白蛋白。
2.CC组出现尿素氮、肌配上升，病理检查出现较严重的肾小球及小
管l’ed质病变。治疗四组(e+o、e+Hss犯、e+MssYZ、C+LSsYZ)尿
素氮、肌配也持续上升，也出现肾功能下降，肾病理损害，但治疗后，
可以降低尿素氮、肌配，对肾脏形态学损害有一定保护作用。Ssyz治
疗三组降尿素氮、肌配作用较吉非罗齐组比较有显著差异(P<0 .01)。
3.对心肌LPL活性及LPL基因表达研究结果表明:CC组心肌LPL
活性浓度及LPLmRNA相对含量较NC组显著下降(P<0.01);治疗四组
(C+G、C十HSSYZ、C+MSSYZ、C+LSSYZ)心肌LPL活性浓度均比
CC组有显著升高，治疗各组之间无显著差异。治疗四组对LPLmRNA表达
显著上调，与CC组相比有显著差异(P<0.01)，治疗各组之间无显著差
异(P> .05)。
结论:SSYZ、吉非罗齐显著调节C盯大鼠血脂水平，SSYZ各治疗
组之间无量效依赖关系。这一改善脂代谢紊乱的作用可能部份是通过提
高LPL活性及LPLmRNA表达上调而实现。SSYZ作用与吉非罗齐作用
相似，在提高白蛋白、改善肾功能及肾脏病理形态损伤的治疗作用较吉
非罗齐好。
Background and Objective: Dyslipidemia occurred in the majority of patients with chronic renal failure. The cause of dyslipidemia is multifactorial. Reduced lipoprotein lipase (LPL) activity played a key role. Dyslipidemia not only leaded patients with renal disease to belonging to a very high cardiovascular risk group but also aggravated renal sclerosis. Dyslipidemia should most likely be subjected to sufficient lipid-lowering therapy in preventing nephropathy process. The purpose of the study was to investigate the therapeutic effect of capsule of shen-shuai-yang-zhen(SSYZ) on lipid metabolism disorder and renal function in rats with 5/6 nephrectomy, Simultaneously, evaluate the cordis Lipoprotein Lipase gene expression, trying to find the therapeutic mechanism of the SSYZ to the CRF rats.
Methods: 1. SD rats were made into CRF model by 5/6 nephrectomy. Rats were randomly sorted into the following groups. Normal control group(NC), CRF control group(CC), Gemfrozil group(C+G), High dose ssyz group(C+HSSYZ), Moderate dose ssyz group(C+MSSYZ), Low dose ssyz group(C+LSSYZ). All rats were treated with corresponding drugs for 4 weeks. During and after the treatment, the general state, serum albumin(AL B), total cholesterol(TC), triglyceride(TG), low density lipoprotein cholest er-ol(LDLc), very low density lipoprotein cholesterol(VLDLc) and high density lipoprotein cholesterol(HDLc) were detected.
2. Blood urea nitrogen contents(BUN) and serum creatinine(SCr) were detected. The kidenys of the rats were used for the study of nephron pathology. Kidney pathological features were observed under microscope.
3. The myocaridum of the rats were used for the study of lipoprotein lipase activity and lipoprotein lipase gene expression, lipoprotein lipase activity was assayed using ultraviolet spectrophotometer, lipoprotein lipase messenger RNA (LPLmRNA) levels were detected by semi-quantitative RT-PCR. blood lipid parameters in CRF rats were detected.
Results: 1. Dyslipidemia occurred in the five CRF groups. SSYZ and Gemfibrozil could improve the general state, HDLc. Besides, TC, TG and LDLc concentrations were decreased (P<0.01) . There were no differentiae among SSYZ and Gemfibrozil groups. There were no dose depend effects in SSYZ groups which can increase serum ALB.
2. Blood urea nitrogen contents(BUN) level, serum creatinine(SCr) level and renal lesions were occured in CC group. SSYZ had better effect on decreasing blood urea nitrogen contents(BUN) level, serum creatinine(SCr) level and on improving renal lesions than Gemfibrozil.
3. The study on the LPL gene expression in heart shows: the LPL gene expression and the LPL activity of CRF rats were significantly upregulated, SSYZ and Gemfibrozil could upregulate the LPL gene expression and the LPL activity. There were no differentiae between SSYZ and Gemfibrozil groups.
Conclusion: The results of the present study provide some evidences that SSYZ and Gemfibrozil can obviously regulate lipids level and improve it in renal insufficiency rats by enhance LPL activity and LPL gene expression. This effect maybe one of the mechanisms that SSYZ adjusts abnormity of lipids of chronic renal failure (CRF) rats. There were no differentia between SSYZ and Gemfibrozil groups. But SSYZ has a better certain effect on preventing nephropathy process, and raising the serum level of ALB.
引文
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56．周恩超，王钢．大黄为主灌肠治疗慢性肾衰的临床和实验研究概况．南京中医药大学学报(自然科学版)，2000，12(2)：127-129．
57．刘文军，杨颖．中医药治疗慢性肾衰机理研究概况．中国中医药科技，2001，8(2)：137．
58．郑丰，黎磊石．大黄对体外肾小管细胞增殖的影响．中华医学杂志，1993，73(6)：34．
59．孔庆志，黄涛，费雁，等．黄芪对大剂量顺铂所致肾毒性防护的实验研究．中国肿瘤临床与康复，1999，34(7)：447-450．
60．孙阳，王玉霞，陈琼华．中药大黄的生化学研究——大黄素甲醚在大
鼠体内的吸收分布和排泄．中国药科大学学报，1998，19(3)：179．
61．郑丰，黎磊石．延缓慢性肾功能不全进展措施的理论和实践．国外医学·内科分册，1990，17(1)：16．
62．倪兆慧，张庆怡，钱家麒，等．黄芪对Ⅳ型胶原蛋白的作用．中华肾脏病杂志，1999，14(3)：273-276．
63．阴建．中药现代研究与临床应用．第1版．北京：人民卫生出版社，1997，597-598．
64．陈孟华，李丽英，潘辑圣，等．黄芪、当归对肾病综合征大鼠肌肉蛋白质代谢的影响．中华肾脏病杂志，1997，13(3)：153．
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70. Shaehter NS.Apoprotein CⅠ and CⅢ as important modulators of Lipoprotein metabolism. Curr-Opin Lipidol, 2001, 12:297.
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72. Weinstock PH, Bisgaier CL, Aalto Setala K, etal. Severe hypertriglyceridemia, reduced high density lipoprotein and neonatal death in lipoprotein lipase knock out mice. J Clin Invest,1995,96:2555-568.
73. Shimada M, Shimano H, Gotoda T, etal. Over expression of human lipoprotein lipase in transgenic mice. Resistance to diet induced
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75. Vilella E, Joven J, Femandezm, etal. Lipoprotein lipase in human plasma is mainly inactive and associated with cholesterol-rich lipoproteins. J Lipid Res, 1993,34(9): 1555-64.
76. Ikeda Y, Takagi A, Nakata Y, etal. A family based study of heperinsulinemia and hypertriglyceridemia in heterozygous lipoprotein lipase deficiency. Clin Claim Acta,,2002,316(1-2): 179-85.
77. Marx N, Duez H, Fruchart JC, etal. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res, 2004,94(9): 1168-78.
78. Portilla D, Dai G, Peters JM, etal. Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. Am J Physiol, 2000, 278:F667-F675.
79．王浴生．中药药理与应用．北京：人民卫生出版社，1983．90，736．
80．李丽英，王海燕，朱世乐，等．黄芪当归对肾病综合征鼠肝白蛋白的表达作用．中华医学杂志，1995，75(5)：276-279．
81．季曙明，黎磊石，季大玺，等．保肾丸治疗长期血透患者临床研究．中国中西医结合杂志，1993，13(2)：71-73．
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83．柯凌．大黄的药理及其在肾脏病中的运用．中国中西医结合杂志，2001，2(6)：347-348．
84．张翥，方敬爱，叶任高．中药的肾保护与肾毒性．中国中西医结合肾病杂志，2001，2(9)：552-556．
85．张景红，黎磊石，万柏珍等．大黄对慢性肾衰病人脂质代谢的影响．中华肾脏病杂志，1993，(3)：133-135．
86．陈佐芳，黄志勇，王以立，等．黄芪和辅酶Q10对肾衰动物作用的实验研究．江苏医药，1989，15(1)：12．
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54．李明旭，王述平，石湘云．长期血液透析和腹膜透析患者血脂水平及相关因素分析．临床内科杂志 2003，20(10)：521-523．
55. Scolnik D, Balfe JW. Initial hypoalbuminemia and hyperlipidemia persist during chronic peritoneal dialysis in children. Petit Dial Int, 1993; 13(2): 136-9.
56．周恩超，王钢．大黄为主灌肠治疗慢性肾衰的临床和实验研究概况．南京中医药大学学报(自然科学版)，2000，12(2)：127-129．
57．刘文军，杨颖．中医药治疗慢性肾衰机理研究概况．中国中医药科技，2001，8(2)：137．
58．郑丰，黎磊石．大黄对体外肾小管细胞增殖的影响．中华医学杂志，1993，73(6)：34．
59．孔庆志，黄涛，费雁，等．黄芪对大剂量顺铂所致肾毒性防护的实验研究．中国肿瘤临床与康复，1999，34(7)：447-450．
60．孙阳，王玉霞，陈琼华．中药大黄的生化学研究——大黄素甲醚在大
鼠体内的吸收分布和排泄．中国药科大学学报，1998，19(3)：179．
61．郑丰，黎磊石．延缓慢性肾功能不全进展措施的理论和实践．国外医学·内科分册，1990，17(1)：16．
62．倪兆慧，张庆怡，钱家麒，等．黄芪对Ⅳ型胶原蛋白的作用．中华肾脏病杂志，1999，14(3)：273-276．
63．阴建．中药现代研究与临床应用．第1版．北京：人民卫生出版社，1997，597-598．
64．陈孟华，李丽英，潘辑圣，等．黄芪、当归对肾病综合征大鼠肌肉蛋白质代谢的影响．中华肾脏病杂志，1997，13(3)：153．
65. Brault D, Noe L, Etienne J, et al. Sequence of rat lipoprotein lipase-cDNA. Gene, 1992,121(2):237-46.
66. Nudel U, Zakut R, Shani M, et al. The nucleotide Sequence of the rat cytoplasmic beta-actin gene. Nucleic Acdis Res, 1983,11(6):1759-71.
67. Amadottir M.Pathogenesis of dyslipoproteinemia in renal insufficiency: the role of lipoprtoein lipase and hepatic lipase. Scand J Clin Lab Invest, 1997,57:15.
68. Obsome JC, et al. Studies on inactivation of lipoprotein lipase; role of the dimer to monomer dissociation. Biochemistry, 1985,24:5606.
69. Ito Y, etal. Hypertriglyceridemia as a result of human apoCⅢ gene expression in tranagenic mice. Science, 1990,249:790.
70. Shaehter NS.Apoprotein CⅠ and CⅢ as important modulators of Lipoprotein metabolism. Curr-Opin Lipidol, 2001, 12:297.
71. Insberg HN, etal. Apolipoprotein B metabolism in subjects with deficiency of apo CⅢ and Al:evidence that apo CⅢ inhibit catabolism of triglyceride rich lipoprotein by lipoprotein lipase in vivo. J Clin Invest, 1986, 78:1287.
72. Weinstock PH, Bisgaier CL, Aalto Setala K, etal. Severe hypertriglyceridemia, reduced high density lipoprotein and neonatal death in lipoprotein lipase knock out mice. J Clin Invest,1995,96:2555-568.
73. Shimada M, Shimano H, Gotoda T, etal. Over expression of human lipoprotein lipase in transgenic mice. Resistance to diet induced
hypertriglyceridemia and hypercholesterolemia. J Biol Chem, 1993, 268:17924-929.
74. Shimada M, Ishibashi S, Gotoda T, etal. Over expression of human lipoprotein lipase protects diabetic transgenic mice from diabetic hypertriglyceridemia and hypercholesterolemia. Arterioscler Thrombvasc Biol,1995,15:1688-694.
75. Vilella E, Joven J, Femandezm, etal. Lipoprotein lipase in human plasma is mainly inactive and associated with cholesterol-rich lipoproteins. J Lipid Res, 1993,34(9): 1555-64.
76. Ikeda Y, Takagi A, Nakata Y, etal. A family based study of heperinsulinemia and hypertriglyceridemia in heterozygous lipoprotein lipase deficiency. Clin Claim Acta,,2002,316(1-2): 179-85.
77. Marx N, Duez H, Fruchart JC, etal. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res, 2004,94(9): 1168-78.
78. Portilla D, Dai G, Peters JM, etal. Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. Am J Physiol, 2000, 278:F667-F675.
79．王浴生．中药药理与应用．北京：人民卫生出版社，1983．90，736．
80．李丽英，王海燕，朱世乐，等．黄芪当归对肾病综合征鼠肝白蛋白的表达作用．中华医学杂志，1995，75(5)：276-279．
81．季曙明，黎磊石，季大玺，等．保肾丸治疗长期血透患者临床研究．中国中西医结合杂志，1993，13(2)：71-73．
82．马骏，林善锬．大黄治疗CRF作用机理探讨．中国中西医结合杂志，1993，13(9)：570-571．
83．柯凌．大黄的药理及其在肾脏病中的运用．中国中西医结合杂志，2001，2(6)：347-348．
84．张翥，方敬爱，叶任高．中药的肾保护与肾毒性．中国中西医结合肾病杂志，2001，2(9)：552-556．
85．张景红，黎磊石，万柏珍等．大黄对慢性肾衰病人脂质代谢的影响．中华肾脏病杂志，1993，(3)：133-135．
86．陈佐芳，黄志勇，王以立，等．黄芪和辅酶Q10对肾衰动物作用的实验研究．江苏医药，1989，15(1)：12．
87．李丽英，王海燕．黄芪当归对肝脏和肾脏功能的保护作用．中华肾脏病杂志，1995，11：372-37．
88．刘杰，陈小珍，阙斌，等．益肾汤对慢性肾功能衰竭大鼠血脂及氧自由基的影响．河北中医，2001，23(2)：150-151．