通脉颗粒治疗嘌呤霉素氨基核苷肾病的药效学研究及机理探讨
|
摘要
肾病综合征(Nephropathy Syndrome,NS)是一种对人类健康危害很大以及给家庭、社会带来沉重负担的临床常见病。临床表现有四大特点:大量蛋白尿、低蛋白血症、高脂血症和明显水肿。在临床治疗方面,激素类、免疫抑制剂仍然是目前西药治疗肾病综合征的常用药物,但激素和免疫抑制剂存在较大的毒副作用且用药时间较长。因此,探索新的治疗途径具有重要的临床价值。中医中药在肾脏病的治疗上有其独到之处,目前已经受到国内外学者的广泛关注。开发和研究新型治疗肾病的中药,也是目前学者们研究的热点。
通脉颗粒是广州中医药大学附属医院治疗肾病综合征的有效方剂,为现代中药制剂。为了进一步阐明通脉颗粒的治疗作用,探讨其作用机制,为其临床应用提供更有力的实验依据,我们进行了本实验研究。
本文分为文献综述和实验研究两部分。在文献综述部分,阐述了中医学对肾病综合征的病名、病因病机、常用治法和方药的认识,以及现代医学对肾病综合征的认识,重点对近几年治疗肾病综合征的研究进展进行了归纳。
在实验研究部分,我们进行了以下实验研究:1、制备了嘌呤霉素氨基核苷(puromycin amino nucleoside,PAN)的肾病模型。2、设计了通脉颗粒治疗PAN 肾病的药效学实验。60 只大鼠分正常组、PAN 肾病模型组、通脉颗粒高、中、低剂量组、蒙诺对照组。各治疗组大鼠均给予灌胃给药 30 天(0.1ml/Kg,每日一次)。观察 24h 尿蛋白定量、血清总蛋白、白蛋白、总胆固醇、甘油三酯、血肌酐、尿素氮、体重、肾脏指数等参数及肾脏病理形态学。3、对通脉颗 粒 治 疗 PAN 肾 病 的 机 理 进 行 初 步 探 讨 。 分 析 了 骨 形 成 发 生 蛋 白 ( Bonemorphogenetic protein, BMPs)BMPs 和及其细胞内信号转导蛋白-Smad 蛋白在 PAN 肾病模型组和药物治疗组肾组织中表达的影响。
实验结果表明,PAN 肾病模型造模成功,适合于通脉颗粒的药效学研究。通脉颗粒可以通过抑制 24h 尿蛋白排泄量,调节血浆蛋白代谢和血脂代谢紊乱,保护肾功能,改善肾小球局灶节段硬化和肾间质纤维化等病理改变,抑制肾组织中 BMPⅡ和 Smads1mRNA 的表达,因而对肾病综合征有良好的治疗作用。
Nephropathy Syndrome(NS) is a worldwide disease with a high incidence anddose harm to human physical and mental health. There are four clinical typesincluding a great deal of albuminuria, low albumen blood diease, high greasediease and apparent dropay. In the aspect of clinical therapy, hormone andimmunosuppressant including cortin, cell toxin, biological preparation are themost of the medicine commonly used in the western medicine to treat NS at theprecent. Due to the biggist toxin and side effect of incretion andimmunosuppressantrelatively looger using drug, and quite quabtitative suffers arenot sensitivity to the therapy. So exploring new approachs of treatment has manyimportant clinical values. Chinese traditional medicine has orginal departments inthe treatment of NS. At the present inside and outside of the country it had beenget the hightly attention. Empoldering and investigating new types of Chinesetraditional medicine to treat NS has become the hotapot in our research.
Tongmai Granule (TM), is used as an effective Chinese traditional medicineclinically in the hospital belong to the Guangzhou University of Chinese traditionalmedicine. In order to provide the experimental basis for the clinical using, we havestudied the suppressive effect of TM on the model induced by puromycin aminonucleoside(PAN).
In the part of paper, we expatiated on the knowledge of the name, pathogeny,pathogenesis, treatment, prescription of NS in the literatures of ancient Chinesetraditional medicine, and correlative knowledge of modern medicine.
Then we carried out the following experiments: 1. Establishing PAN-treatedmodel. 2. The preventive effects of Tong-mai Granule on the model induced byPAN were evaluated. Sixty rats were divided into six groups. They are normalcontrol group、PAN-model group、Tong-mai Granule group of high, middle, lowdosage, ACE group, Urine samples were collected from the rats in metabolic cageson days 5, 10, 15, 20, 25 and 30 after the injection of PAN. All rats were sacrificed31 days after the injection of PAN for blood biochemistry, RNA preparation, lightmicroscopy and electrical microscopy of the kidneys. 3 、 We assayed theexperission of Bone morphogenetic protein(BMPs) and intracellular protein-Smadin the kidney.
Our study indicates that we make the PAN-model successfully.The results ofthirty day’s observation showed that Tong-mai Granule could decrease urinary
protein excretion, regulate abnormal blood fat metabolism, save renal function andimprove pathological changes in PAN model rats, inhibit of expression of BMPRIIand Smad1mRNA in the kidneys.
通脉颗粒是广州中医药大学附属医院治疗肾病综合征的有效方剂,为现代中药制剂。为了进一步阐明通脉颗粒的治疗作用,探讨其作用机制,为其临床应用提供更有力的实验依据,我们进行了本实验研究。
本文分为文献综述和实验研究两部分。在文献综述部分,阐述了中医学对肾病综合征的病名、病因病机、常用治法和方药的认识,以及现代医学对肾病综合征的认识,重点对近几年治疗肾病综合征的研究进展进行了归纳。
在实验研究部分,我们进行了以下实验研究:1、制备了嘌呤霉素氨基核苷(puromycin amino nucleoside,PAN)的肾病模型。2、设计了通脉颗粒治疗PAN 肾病的药效学实验。60 只大鼠分正常组、PAN 肾病模型组、通脉颗粒高、中、低剂量组、蒙诺对照组。各治疗组大鼠均给予灌胃给药 30 天(0.1ml/Kg,每日一次)。观察 24h 尿蛋白定量、血清总蛋白、白蛋白、总胆固醇、甘油三酯、血肌酐、尿素氮、体重、肾脏指数等参数及肾脏病理形态学。3、对通脉颗 粒 治 疗 PAN 肾 病 的 机 理 进 行 初 步 探 讨 。 分 析 了 骨 形 成 发 生 蛋 白 ( Bonemorphogenetic protein, BMPs)BMPs 和及其细胞内信号转导蛋白-Smad 蛋白在 PAN 肾病模型组和药物治疗组肾组织中表达的影响。
实验结果表明,PAN 肾病模型造模成功,适合于通脉颗粒的药效学研究。通脉颗粒可以通过抑制 24h 尿蛋白排泄量,调节血浆蛋白代谢和血脂代谢紊乱,保护肾功能,改善肾小球局灶节段硬化和肾间质纤维化等病理改变,抑制肾组织中 BMPⅡ和 Smads1mRNA 的表达,因而对肾病综合征有良好的治疗作用。
Nephropathy Syndrome(NS) is a worldwide disease with a high incidence anddose harm to human physical and mental health. There are four clinical typesincluding a great deal of albuminuria, low albumen blood diease, high greasediease and apparent dropay. In the aspect of clinical therapy, hormone andimmunosuppressant including cortin, cell toxin, biological preparation are themost of the medicine commonly used in the western medicine to treat NS at theprecent. Due to the biggist toxin and side effect of incretion andimmunosuppressantrelatively looger using drug, and quite quabtitative suffers arenot sensitivity to the therapy. So exploring new approachs of treatment has manyimportant clinical values. Chinese traditional medicine has orginal departments inthe treatment of NS. At the present inside and outside of the country it had beenget the hightly attention. Empoldering and investigating new types of Chinesetraditional medicine to treat NS has become the hotapot in our research.
Tongmai Granule (TM), is used as an effective Chinese traditional medicineclinically in the hospital belong to the Guangzhou University of Chinese traditionalmedicine. In order to provide the experimental basis for the clinical using, we havestudied the suppressive effect of TM on the model induced by puromycin aminonucleoside(PAN).
In the part of paper, we expatiated on the knowledge of the name, pathogeny,pathogenesis, treatment, prescription of NS in the literatures of ancient Chinesetraditional medicine, and correlative knowledge of modern medicine.
Then we carried out the following experiments: 1. Establishing PAN-treatedmodel. 2. The preventive effects of Tong-mai Granule on the model induced byPAN were evaluated. Sixty rats were divided into six groups. They are normalcontrol group、PAN-model group、Tong-mai Granule group of high, middle, lowdosage, ACE group, Urine samples were collected from the rats in metabolic cageson days 5, 10, 15, 20, 25 and 30 after the injection of PAN. All rats were sacrificed31 days after the injection of PAN for blood biochemistry, RNA preparation, lightmicroscopy and electrical microscopy of the kidneys. 3 、 We assayed theexperission of Bone morphogenetic protein(BMPs) and intracellular protein-Smadin the kidney.
Our study indicates that we make the PAN-model successfully.The results ofthirty day’s observation showed that Tong-mai Granule could decrease urinary
protein excretion, regulate abnormal blood fat metabolism, save renal function andimprove pathological changes in PAN model rats, inhibit of expression of BMPRIIand Smad1mRNA in the kidneys.
引文
1. 杨 翠 兰 , 裘 沛 然 . 治 疗 慢 性 肾 炎 的 思 路 与 方 法 . 中 医 杂 志 , 1996 , 27(8):497-498
2. 刘新祥,毛以林,周珂,等.脾肾双补法为主综合治疗原发性肾病综合征临 床疗效观察.中国中西医结合肾病杂志,2001,2(3):149-150
3. 陈 志 强 . 中 医 药 治 疗 肾 病 综 合 征 的 临 床 研 究 进 展 . 天 津 中 医 , 1996 , 13(3):42-45
4. 李红叶,孙福恩,崔可飞,等.水蛭治疗小儿原发性肾病综合征高粘血症的 疗效观察.中国实用儿科杂志,1998,13(3):165
5. 朱彩风,徐琳,陈洪宇,等.肾病瘀血的中医诊治.浙江中医学院学报,1998, 22(3):56
6. 周莉雅,倪青,时振声.时振声教授从脾论治肾脏疾病的经验.中国中西医 结合杂志,1996,16(4):246
7. 杜胜滨,曲秀娟,周亚宾,等.近十年来肾病综合征的中医临床研究进展. 中医药信息,1996,13(6):31-32
8. 阳晓,叶任高,刘冠贤,等.38 年中西医结合治疗肾脏病的临床和实验研究. 中山医科大学学报,2000,21(6):401-408
9. 叶任高,余俊文,张芸青.中西医结合治疗成人原发性肾病综合征 134 例观 察.中国中西医结合杂志,1993,13(2):184
10.郑淑贞.浅谈中西医结合治疗肾病综合征 22 例体会.中国中西医结合肾病 杂志,2004,5(1):48
11.张勉之,张大宁,刘树松,等.补肾活血法治疗难治性肾病综合征临床观察. 中国实验方剂学杂志,2004,10(3):53
12.田景友,程广舟,彭庆峰.中西医结合治疗原发性肾病综合征 32 例临床观 察. 山东医药,2004,44(4):48
13.杨尚凌.无比山药丸加减治疗肾病综合征 36 例.湖南中医杂志,2004,20 (1):41
14.卢娟娟,蔡楚丹,许平辉,等.中西医结合治疗原发性肾病综合征的疗效观 察,中国中西医结合肾病杂志,2002,3(3):157
15.徐达良,刘晨曦.柴苓汤合桃红四物汤治疗肾病综合征高脂血症的现代研究. 中西医结合杂志,2004,13(6),227
16.魏小萌.健脾益肾豁痰化瘀方治疗肾病综合征 48 例.陕西中医,2003,24 (4):306
17.赖申昌,卢玲,马晓露,等.中西医结合治疗难治性肾病综合征 24 例.山西 中医,2003,19(2):33
18.叶任高.肾病综合征的中西医结合治疗.江苏中医,1999,20(9):3
19.刘咸峰,中西医结合治疗难治性肾病综合征临床观察.现代中西医结合杂志,2004,13(2):173
20.李凤珍,王小平,钟丽雁.中西医结合治疗肾病综合征(激素依赖型)20 例. 实用中医内科杂志,2004,18(1):42
21.贾在金.中西医结合治疗难治性肾病综合征 60 例.中国中西医结合杂志, 2002,22(3):227
22.曹元奎.芪蛭黄七子汤佐治儿童突发性肾病综合征 80 例.中国中医药科技, 2004,11(1):58
23.陈树真,郭更新,呼延云,等.肾必康口服液治疗肾病综合征的临床研究. 中 国中西医结合急救杂志,2000,7(4):206
24.张德暄.小儿肾病综合征发病机制的研究进展.临床儿科杂志,1995,13(5): 350～360
25.陈述枚.肾病综合征发病机制的新动向[J]中华儿科杂志,2001,39(12):705～706
26.Smoyer WE, Mundel P. Regulation of podocyte structure during the development of nephritic syndrome. J Mol1 Yed. 1998, 76: 172～183
27.Garin EH. Circulation mediators of proteinuria in idiopathic minimal lesion nephrotic syndrome. Pediatr Mphrol, 2000, 14: 872～878
28.Lu SG, Jiang X5, Hu M, et al. Na~+- k~+- ATPase activity: role in the impaired sodium excretion of experimental nephrosis in rats.Chin 1A d J, 1994, 107: 536～540
29.卢思广,姜新酞,高远赋.肾素-血管紧张素-醛固酮系统在阿霉素肾病大 鼠肾钠储留中的作用.中华儿科杂志,1995,33:276～278
30.Feraile E, Vogt B, Rousselot M, et al. Mechanism of enhanced Na~+-k~+-ATPase activity in cortical collecting duct from rats with nephritic syndrome. J Chin Invest, 1993, 91:1295～1300
31.卢思广,夏志强,董晨,等.抗利尿激素在阿霉素肾病大鼠水储留机制中的 作用.中华儿科杂志,2001,39(1):31～34
32.刘雨虹,潘中允.肾病儿童水肿发生机制的探讨.中华肾脏病杂志,1990, 6(2):66～69
33.Smith JD, Hayslett JP.Reversible renal failure in the nephritic syndrome. Am J Kidney Dis, 1992, 19: 201
34.侯凡凡,张训.肾脏多巴胺在肾病综合征水钠储留中的作用.中华内科杂志, 1992,31(9):552～555
35.Peterson C, Madsen B, et al .Atrial natriuretic peptide and the renal response to hypervolemia in nephritic humans. Kidney Int, 1988, 34: 825
36.尹莲芳,蹼家伉,弓玉祥,等.黄蜀葵花对阿霉素肾病大鼠钠储留改善作用 的机制.中华肾脏病杂志,1999,15(5):324
37.Frank S, Antonwiczl, Craig JM, Metcoff J.Experimental nephritic syndrome induced in rat by a minonucleoside.Renol lesion and body electrolyte composition. J Proc.Soc.Exp.Biol.Med, 1955, 89: 424
38.Diamond JR, Bonventre JV, Karnovski M. A role for oxygen free radicals in aminonucleoside nephrosis.Kidney Int, 1986, 29: 478-483
39.申洪,沈忠英.实用生物体视学技术.广州:中山大学出版社,1991.159-178
40.Liang K, Vaziri ND.Gene expression of Lipoprotein Lipase in experimental nephrosis.J Lab Clin Med, 1997, 130: 387-394
41.Bertani T, Poggi A, Pozzoni R, et al. Adriamycin-induced nephritic syndrome in rats. Laboratory Ivestigation, 1982, 46: 16-23
42.Myazono K, Kusanagi K, Inoue H.J Cell Physiol, 2001,187: 265-76
43.AnJa N, Sylke H, Marcelo E, et a1. J Biol Chem, 2002, 277(7): 5330-5338
44.Kawabata M, Imamura T, Myazono K. Cytokine Growth Factor Rev, 1988, 9(1): 49-61
45.Kitten AM, Kreisberg JI , Olson MS. J Cell Physiol, 1999, 181(3): 410-415
46.Piscione TD, Phan T, Rosenblum ND. Am J Physiol Renal Physicall, 2001, 280: Fl9-F33
47.Gould SE, Day M, Jones SS.Kidney Int, 2002, 61(1): 51-60
48.Choundhury GG, Kim YS, Simon M, et a1. J Biol Chem, 1999, 274(16): 10897-10902
49.Ghosh CG, Jin DC, Kim YS, et al. Biochem Biophys Res Commun, 1999, 258: 490-496
50.Simon M, Maresh JG, Harris SE, et a1. Am J Physio1, 1999, 276: F382-F389
51.Vukicevic S, Basic V, Rogic D, et al .J Gin Invest, 1998, 102: 202-214
52.Morrissey J, Hruska K,Gho G,et al. J Am Soc Nephrol,2002,13 Suppl1:S14-S21
53.Hruska KA, Guo G, Wozniak M, et al. Am J Physiol Renal Physiol, 2000, 279(1):F130-43
54.Wang SN, Lapage J, Hirschberg R. J Am Soc Nephro1, 2001, 12:2392-9
55.Lund RJ, Davies MR, Hruska KA.Curr Opin Nephrol Hypertens, 2002, 11:31-6
56.McMahon R, Murphy M, Clarkson M, et, al.JBio1 Chem, 2000, 275:9901-9904
57.Karkar AM, Allen A, Cook T, et al Anternational Society of Nephrology, 1999, 55(6): 2555
2. 刘新祥,毛以林,周珂,等.脾肾双补法为主综合治疗原发性肾病综合征临 床疗效观察.中国中西医结合肾病杂志,2001,2(3):149-150
3. 陈 志 强 . 中 医 药 治 疗 肾 病 综 合 征 的 临 床 研 究 进 展 . 天 津 中 医 , 1996 , 13(3):42-45
4. 李红叶,孙福恩,崔可飞,等.水蛭治疗小儿原发性肾病综合征高粘血症的 疗效观察.中国实用儿科杂志,1998,13(3):165
5. 朱彩风,徐琳,陈洪宇,等.肾病瘀血的中医诊治.浙江中医学院学报,1998, 22(3):56
6. 周莉雅,倪青,时振声.时振声教授从脾论治肾脏疾病的经验.中国中西医 结合杂志,1996,16(4):246
7. 杜胜滨,曲秀娟,周亚宾,等.近十年来肾病综合征的中医临床研究进展. 中医药信息,1996,13(6):31-32
8. 阳晓,叶任高,刘冠贤,等.38 年中西医结合治疗肾脏病的临床和实验研究. 中山医科大学学报,2000,21(6):401-408
9. 叶任高,余俊文,张芸青.中西医结合治疗成人原发性肾病综合征 134 例观 察.中国中西医结合杂志,1993,13(2):184
10.郑淑贞.浅谈中西医结合治疗肾病综合征 22 例体会.中国中西医结合肾病 杂志,2004,5(1):48
11.张勉之,张大宁,刘树松,等.补肾活血法治疗难治性肾病综合征临床观察. 中国实验方剂学杂志,2004,10(3):53
12.田景友,程广舟,彭庆峰.中西医结合治疗原发性肾病综合征 32 例临床观 察. 山东医药,2004,44(4):48
13.杨尚凌.无比山药丸加减治疗肾病综合征 36 例.湖南中医杂志,2004,20 (1):41
14.卢娟娟,蔡楚丹,许平辉,等.中西医结合治疗原发性肾病综合征的疗效观 察,中国中西医结合肾病杂志,2002,3(3):157
15.徐达良,刘晨曦.柴苓汤合桃红四物汤治疗肾病综合征高脂血症的现代研究. 中西医结合杂志,2004,13(6),227
16.魏小萌.健脾益肾豁痰化瘀方治疗肾病综合征 48 例.陕西中医,2003,24 (4):306
17.赖申昌,卢玲,马晓露,等.中西医结合治疗难治性肾病综合征 24 例.山西 中医,2003,19(2):33
18.叶任高.肾病综合征的中西医结合治疗.江苏中医,1999,20(9):3
19.刘咸峰,中西医结合治疗难治性肾病综合征临床观察.现代中西医结合杂志,2004,13(2):173
20.李凤珍,王小平,钟丽雁.中西医结合治疗肾病综合征(激素依赖型)20 例. 实用中医内科杂志,2004,18(1):42
21.贾在金.中西医结合治疗难治性肾病综合征 60 例.中国中西医结合杂志, 2002,22(3):227
22.曹元奎.芪蛭黄七子汤佐治儿童突发性肾病综合征 80 例.中国中医药科技, 2004,11(1):58
23.陈树真,郭更新,呼延云,等.肾必康口服液治疗肾病综合征的临床研究. 中 国中西医结合急救杂志,2000,7(4):206
24.张德暄.小儿肾病综合征发病机制的研究进展.临床儿科杂志,1995,13(5): 350～360
25.陈述枚.肾病综合征发病机制的新动向[J]中华儿科杂志,2001,39(12):705～706
26.Smoyer WE, Mundel P. Regulation of podocyte structure during the development of nephritic syndrome. J Mol1 Yed. 1998, 76: 172～183
27.Garin EH. Circulation mediators of proteinuria in idiopathic minimal lesion nephrotic syndrome. Pediatr Mphrol, 2000, 14: 872～878
28.Lu SG, Jiang X5, Hu M, et al. Na~+- k~+- ATPase activity: role in the impaired sodium excretion of experimental nephrosis in rats.Chin 1A d J, 1994, 107: 536～540
29.卢思广,姜新酞,高远赋.肾素-血管紧张素-醛固酮系统在阿霉素肾病大 鼠肾钠储留中的作用.中华儿科杂志,1995,33:276～278
30.Feraile E, Vogt B, Rousselot M, et al. Mechanism of enhanced Na~+-k~+-ATPase activity in cortical collecting duct from rats with nephritic syndrome. J Chin Invest, 1993, 91:1295～1300
31.卢思广,夏志强,董晨,等.抗利尿激素在阿霉素肾病大鼠水储留机制中的 作用.中华儿科杂志,2001,39(1):31～34
32.刘雨虹,潘中允.肾病儿童水肿发生机制的探讨.中华肾脏病杂志,1990, 6(2):66～69
33.Smith JD, Hayslett JP.Reversible renal failure in the nephritic syndrome. Am J Kidney Dis, 1992, 19: 201
34.侯凡凡,张训.肾脏多巴胺在肾病综合征水钠储留中的作用.中华内科杂志, 1992,31(9):552～555
35.Peterson C, Madsen B, et al .Atrial natriuretic peptide and the renal response to hypervolemia in nephritic humans. Kidney Int, 1988, 34: 825
36.尹莲芳,蹼家伉,弓玉祥,等.黄蜀葵花对阿霉素肾病大鼠钠储留改善作用 的机制.中华肾脏病杂志,1999,15(5):324
37.Frank S, Antonwiczl, Craig JM, Metcoff J.Experimental nephritic syndrome induced in rat by a minonucleoside.Renol lesion and body electrolyte composition. J Proc.Soc.Exp.Biol.Med, 1955, 89: 424
38.Diamond JR, Bonventre JV, Karnovski M. A role for oxygen free radicals in aminonucleoside nephrosis.Kidney Int, 1986, 29: 478-483
39.申洪,沈忠英.实用生物体视学技术.广州:中山大学出版社,1991.159-178
40.Liang K, Vaziri ND.Gene expression of Lipoprotein Lipase in experimental nephrosis.J Lab Clin Med, 1997, 130: 387-394
41.Bertani T, Poggi A, Pozzoni R, et al. Adriamycin-induced nephritic syndrome in rats. Laboratory Ivestigation, 1982, 46: 16-23
42.Myazono K, Kusanagi K, Inoue H.J Cell Physiol, 2001,187: 265-76
43.AnJa N, Sylke H, Marcelo E, et a1. J Biol Chem, 2002, 277(7): 5330-5338
44.Kawabata M, Imamura T, Myazono K. Cytokine Growth Factor Rev, 1988, 9(1): 49-61
45.Kitten AM, Kreisberg JI , Olson MS. J Cell Physiol, 1999, 181(3): 410-415
46.Piscione TD, Phan T, Rosenblum ND. Am J Physiol Renal Physicall, 2001, 280: Fl9-F33
47.Gould SE, Day M, Jones SS.Kidney Int, 2002, 61(1): 51-60
48.Choundhury GG, Kim YS, Simon M, et a1. J Biol Chem, 1999, 274(16): 10897-10902
49.Ghosh CG, Jin DC, Kim YS, et al. Biochem Biophys Res Commun, 1999, 258: 490-496
50.Simon M, Maresh JG, Harris SE, et a1. Am J Physio1, 1999, 276: F382-F389
51.Vukicevic S, Basic V, Rogic D, et al .J Gin Invest, 1998, 102: 202-214
52.Morrissey J, Hruska K,Gho G,et al. J Am Soc Nephrol,2002,13 Suppl1:S14-S21
53.Hruska KA, Guo G, Wozniak M, et al. Am J Physiol Renal Physiol, 2000, 279(1):F130-43
54.Wang SN, Lapage J, Hirschberg R. J Am Soc Nephro1, 2001, 12:2392-9
55.Lund RJ, Davies MR, Hruska KA.Curr Opin Nephrol Hypertens, 2002, 11:31-6
56.McMahon R, Murphy M, Clarkson M, et, al.JBio1 Chem, 2000, 275:9901-9904
57.Karkar AM, Allen A, Cook T, et al Anternational Society of Nephrology, 1999, 55(6): 2555