一氧化氮与肥胖相关性肾病关系的研究
摘要
研究背景和目的:
随着我国经济的快速发展、人们饮食习惯及生活方式的改变,儿童及成人肥胖症的发病率逐年上升。肥胖已成为一种疾病,它不仅是睡眠呼吸暂停综合症、高脂血症、高血压病、冠状血管病、胰岛抵抗及糖尿病的高危因素,还可以引起肾脏损害,即肥胖相关性肾病(obesity-relatedglomerulonephropathy,ORG)。ORG一词首先由Cohen提出,他描述了肾小球肥大为ORG的突出表现,此外可有轻度细胞加多系膜区不同程度加宽,有时出现局灶节段性硬化。ORG起病隐匿,首先出现微量清蛋白尿,其发生率随肥胖程度递增,随病情进展出现显性蛋白尿,少数可达肾病水平蛋白尿。持续存在ORG可逐步出现肾功能减退,部分病人亦可发展为严重的肾功能不全。因此早期诊断肥胖相关性肾病有极其重要的意义。ORG的发病机制目前尚未完全阐明。研究发现,在动物及人类的慢性肾脏疾病中一氧化氮(NO)的合成是减少的。然而,有关NO是否参与肥胖相关性肾病的发生发展,国内外报道较少。为此,本研究的目的是:采用高脂饮食,建立肥胖大鼠模型,观察其血清、肾组织NO含量及尿中NO代谢产物排泄量(UNOxV urinary nitrite+nitrate excretion)的变化及其与肾脏功能和肾组织形态学的关系,探讨NO在肥胖相关性肾病发病中的作用,为肥胖相关性肾病的早期诊断和治疗提供一定的理论依据。
材料与研究方法:
将离乳28天的16只健康雄性Wistar大鼠随机分成两组,分别称为普通对照组(A组,n=8)及肥胖组(B组,n=8),分别给予普通饮食及高脂饮食喂养。20周后处死全部大鼠,处死前留取24小时尿量,无菌条件下下腔静脉取血、取双肾,右肾取100mg肾皮质制成10%肾组织匀浆,左肾称重、部分皮质用10%的中性福尔马林溶液固定以备HE染色。分别观察以下指标:
1、测量体重及身长,计算Lee指数、左肾指数(左肾重/体重)。
2、测定血总胆固醇(TCH)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、肌酐(Scr)、尿素氮(BUN)、血糖(Glu)。
3、留取24小时尿液测定尿肌酐(Ucr)、尿蛋白(UPE)定量,并计算内生肌酐清除率Ccr(用以代表肾小球滤过率GFR)。
4、分别以硝酸还原酶间接法测定两组大鼠血、肾组织匀浆NO含量以及尿NO代谢产物排泄量(UNOxV)。
5、左肾皮质石蜡包埋后切片,做常规HE染色,光镜下观察肾组织形态学改变,利用图像分析仪(optimas)测定肾小球截面积。
研究结果:
1、肥胖组大鼠Lee指数、左肾指数明显高于对照组(P＜0.01)。
2、肥胖组血总胆固醇(TCH)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)明显高于对照组(P＜0.01);高密度脂蛋白胆固醇(HDL-C)明显低于对照组(P＜0.01);血糖高于对照组,但差异无显著性(P＞0.05)。
3、24小时尿蛋白定量明显高于对照组(P＜0.01);内生肌酐清除率Ccr高于对照组(P＜0.01)。
4、血及肾组织匀浆NO水平明显低于对照组(P＜0.01),尿NO代谢产物排泄量(UNOxV)亦低于对照组(P＜0.01)。
5、肥胖组大鼠存在明显的系膜细胞增生,球囊粘连、狭窄,间质小动脉内膜增生、部分透明变性,肾小球平均截面积明显增大(P＜0.01)。
结论:
1、肥胖组大鼠Lee指数升高提示肥胖模型建成。
2、肥胖组大鼠TCH、TG、LDL-C升高、HDL-C降低,提示存在明显的脂代谢紊乱。
3、肥胖大鼠血清NO降低、肾组织匀浆NO含量及尿中NO代谢产物排出量均明显降低,提示肥胖大鼠体内NO合成不足,存在血管内皮和微血管内皮功能障碍。
4、肥胖组大鼠24小时尿蛋白定量明显增加、内生肌酐清除率升高、同时肾组织形态学表现为肾小球肥大,明显的系膜细胞增生,球囊粘连、狭窄,间质小动脉内膜增生、部分透明变性,提示肥胖大鼠存在肾脏损害。
5、相关分析结果,NO可能与肥胖相关性肾病的发生密切相关。
Investigation background and objective:
In our country,with the rapid development of economic、change of people's diet habit and life style,the incidence of obesity have risen in children and adult year by year.Obesity has already been a disease which not only is the risky factor for sleep apnea syndrome、hyperlipoidemia、hypertensive disease、coronary vessel disease、glomeruli pancreatici resistance,but can damage kidey,i.e,obesity-related glomerulonephropathy(ORG).ORG was preferred first by Cohen,who described that glomerulum hypertrophy was conspicuous appearance,besides,many mesangial regions broaden in different extent and focal segmental sclerosis exist in some time.The onset of ORG is delitescent.At first,there is a microamount of albuminuria whose incidence increases progressively with obesity.With the advancement of pathogenetic condition,there appears dominant albuminuria,and a part can reach multi-albuminuria of nephropathy.The patients who have persistent existing ORG appear renal hypofunction gradually,a part of which aggravate to severe renal inadequacy.Therefore,there is vital significance for early diagnosis of ORG.The pathogenesis of ORG has not yet been illuminated wholly.There have been some researches discovered that nitric oxide's(NO)synthesis decreased in chronic renal disease in animal and people.However,the report of whether or not the NO participates the genesis and development in ORG is less in domestic and abroad.So,in our study,we employed a model of Wistar mice with obesity-related glomerulonephropathy given high fat diet,to observe whether or not there was the change of nitric oxide(NO)content in blood serum,nephridial tissue and urinary nitrite+nitrate excretion(UNOxV),and the relationship with the renal function and renal histomorphology in order to investigate NO'effect on ORG which can provide theories basis for the early diagnosis and therapy of ORG.
Materials and Methods:
16 4-week-old healthy weaning male mice were randomly divided into 2 groups,8/group,including:normal control(A,n=8)and obesity group(B,n=8); each mouse in group A was given full diet,while in group B was given high fat diet.After 20 weeks,all mice were killed and before that,we remained urinary volume of 24 hours.We got blood in inferior caval vein on sterile condition. After we got both kidneys,100mg renal cortex of right kidey was made into nephridial tissue homogenate,while in left kidey,part of cortex was fixed by neutral- formaldehyde to get ready for HE dyeing.These indexes were observed respectively:
1.Body weight and length were obtained to get index of Lee and left renal index(left kidney weight/body weight);
2.The content of cholesterol total(TCH)、triglyceride(TG)、low density lipoprotein cholesterol(LDL-C)、high density lipoprotein cholesterol(HDL-C)、creatinine(Scr)、urea nitrogen(BUN)and blood glucose (Glu)were detected.
3.By urine creatinine(Ucr)and urine protein(UPE)quantitation in 24 hours,creatinine clearance was calculated(to represent glomerular filtration rate, GFR).
4.In both groups,nitric oxide(NO)content in blood、nephridial tissue and urinary nitrite+nitrate excretion(UNOxV)were acquired by nitrate disoxidation method.
5.After left renal cortex was imbedded by paraffin and dyed by HE, histomorphology examination of kidney by optical microscope,glomerulum section area was determined by image analysator.
Results:
1.In obesity group,the level of index of Lee and left renal index was higher significantly(P＜0.01).
2.In obesity group,cholesterol total(TCH),triglyceride(TG)and low density lipoprotein cholesterol(LDL-C)was higher significantly(P＜0.01);high density lipoprotein cholesterol(HDL-C)was lower obviously(P＜0.01);blood glucose higher,but not significant(P＞0.05).
3.In obesity group,urine protein quantitation in 24 hours was higher in group B than group A obviously(P＜0.01);while creatinine clearance(Ccr) higher(P＜0.01).
4.In obesity group,nitric oxide(NO)content in blood、nephridial tissue was lower than group A evidently(P＜0.01);And urinary nitrite+nitrate excretion(UNOxV)was also lower in group B(P＜0.01).
5.In group B,there were evident intercapillary cellular proliferation, sacculus proprius adhesion、stegnosis,interstitial arteriole hyperplasia endothelialis,hyaline degeneration and glomerulum average section area increasing obviously(P＜0.01).
Conclusions:
1.In obesity group,the advancement of Lee index showed obesity model successful.
2.In obesity group,TCH,TG,LDL-C increasing and HDL-C lowering showed conspicuous lipid metabolism disorder.
3.In obesity group,there was obvious loss of nitric oxide(NO)in blood、nephridial tissue and urinary nitrite+nitrate excretion(UNOxV)which can tell us that NO' synthesis insufficient,blood vessel endothelium and capillary vessel endothelium functional disturbance.
4.In obesity group,the phenomenon that urine protein quantitation in 24 hours higher、creatinine clearance(Ccr)higher、glomerulum hypertrophy、evident intercapillary cellular proliferation,sacculus proprius adhesion、stegnosis,interstitial arteriole hyperplasia endothelialis,hyaline degeneration prompted kidney damage.
5.According to correlation analytic result,we can get NO may be closely relevant to obesity-related glomerulonephropathy.
随着我国经济的快速发展、人们饮食习惯及生活方式的改变,儿童及成人肥胖症的发病率逐年上升。肥胖已成为一种疾病,它不仅是睡眠呼吸暂停综合症、高脂血症、高血压病、冠状血管病、胰岛抵抗及糖尿病的高危因素,还可以引起肾脏损害,即肥胖相关性肾病(obesity-relatedglomerulonephropathy,ORG)。ORG一词首先由Cohen提出,他描述了肾小球肥大为ORG的突出表现,此外可有轻度细胞加多系膜区不同程度加宽,有时出现局灶节段性硬化。ORG起病隐匿,首先出现微量清蛋白尿,其发生率随肥胖程度递增,随病情进展出现显性蛋白尿,少数可达肾病水平蛋白尿。持续存在ORG可逐步出现肾功能减退,部分病人亦可发展为严重的肾功能不全。因此早期诊断肥胖相关性肾病有极其重要的意义。ORG的发病机制目前尚未完全阐明。研究发现,在动物及人类的慢性肾脏疾病中一氧化氮(NO)的合成是减少的。然而,有关NO是否参与肥胖相关性肾病的发生发展,国内外报道较少。为此,本研究的目的是:采用高脂饮食,建立肥胖大鼠模型,观察其血清、肾组织NO含量及尿中NO代谢产物排泄量(UNOxV urinary nitrite+nitrate excretion)的变化及其与肾脏功能和肾组织形态学的关系,探讨NO在肥胖相关性肾病发病中的作用,为肥胖相关性肾病的早期诊断和治疗提供一定的理论依据。
材料与研究方法:
将离乳28天的16只健康雄性Wistar大鼠随机分成两组,分别称为普通对照组(A组,n=8)及肥胖组(B组,n=8),分别给予普通饮食及高脂饮食喂养。20周后处死全部大鼠,处死前留取24小时尿量,无菌条件下下腔静脉取血、取双肾,右肾取100mg肾皮质制成10%肾组织匀浆,左肾称重、部分皮质用10%的中性福尔马林溶液固定以备HE染色。分别观察以下指标:
1、测量体重及身长,计算Lee指数、左肾指数(左肾重/体重)。
2、测定血总胆固醇(TCH)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、肌酐(Scr)、尿素氮(BUN)、血糖(Glu)。
3、留取24小时尿液测定尿肌酐(Ucr)、尿蛋白(UPE)定量,并计算内生肌酐清除率Ccr(用以代表肾小球滤过率GFR)。
4、分别以硝酸还原酶间接法测定两组大鼠血、肾组织匀浆NO含量以及尿NO代谢产物排泄量(UNOxV)。
5、左肾皮质石蜡包埋后切片,做常规HE染色,光镜下观察肾组织形态学改变,利用图像分析仪(optimas)测定肾小球截面积。
研究结果:
1、肥胖组大鼠Lee指数、左肾指数明显高于对照组(P＜0.01)。
2、肥胖组血总胆固醇(TCH)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)明显高于对照组(P＜0.01);高密度脂蛋白胆固醇(HDL-C)明显低于对照组(P＜0.01);血糖高于对照组,但差异无显著性(P＞0.05)。
3、24小时尿蛋白定量明显高于对照组(P＜0.01);内生肌酐清除率Ccr高于对照组(P＜0.01)。
4、血及肾组织匀浆NO水平明显低于对照组(P＜0.01),尿NO代谢产物排泄量(UNOxV)亦低于对照组(P＜0.01)。
5、肥胖组大鼠存在明显的系膜细胞增生,球囊粘连、狭窄,间质小动脉内膜增生、部分透明变性,肾小球平均截面积明显增大(P＜0.01)。
结论:
1、肥胖组大鼠Lee指数升高提示肥胖模型建成。
2、肥胖组大鼠TCH、TG、LDL-C升高、HDL-C降低,提示存在明显的脂代谢紊乱。
3、肥胖大鼠血清NO降低、肾组织匀浆NO含量及尿中NO代谢产物排出量均明显降低,提示肥胖大鼠体内NO合成不足,存在血管内皮和微血管内皮功能障碍。
4、肥胖组大鼠24小时尿蛋白定量明显增加、内生肌酐清除率升高、同时肾组织形态学表现为肾小球肥大,明显的系膜细胞增生,球囊粘连、狭窄,间质小动脉内膜增生、部分透明变性,提示肥胖大鼠存在肾脏损害。
5、相关分析结果,NO可能与肥胖相关性肾病的发生密切相关。
Investigation background and objective:
In our country,with the rapid development of economic、change of people's diet habit and life style,the incidence of obesity have risen in children and adult year by year.Obesity has already been a disease which not only is the risky factor for sleep apnea syndrome、hyperlipoidemia、hypertensive disease、coronary vessel disease、glomeruli pancreatici resistance,but can damage kidey,i.e,obesity-related glomerulonephropathy(ORG).ORG was preferred first by Cohen,who described that glomerulum hypertrophy was conspicuous appearance,besides,many mesangial regions broaden in different extent and focal segmental sclerosis exist in some time.The onset of ORG is delitescent.At first,there is a microamount of albuminuria whose incidence increases progressively with obesity.With the advancement of pathogenetic condition,there appears dominant albuminuria,and a part can reach multi-albuminuria of nephropathy.The patients who have persistent existing ORG appear renal hypofunction gradually,a part of which aggravate to severe renal inadequacy.Therefore,there is vital significance for early diagnosis of ORG.The pathogenesis of ORG has not yet been illuminated wholly.There have been some researches discovered that nitric oxide's(NO)synthesis decreased in chronic renal disease in animal and people.However,the report of whether or not the NO participates the genesis and development in ORG is less in domestic and abroad.So,in our study,we employed a model of Wistar mice with obesity-related glomerulonephropathy given high fat diet,to observe whether or not there was the change of nitric oxide(NO)content in blood serum,nephridial tissue and urinary nitrite+nitrate excretion(UNOxV),and the relationship with the renal function and renal histomorphology in order to investigate NO'effect on ORG which can provide theories basis for the early diagnosis and therapy of ORG.
Materials and Methods:
16 4-week-old healthy weaning male mice were randomly divided into 2 groups,8/group,including:normal control(A,n=8)and obesity group(B,n=8); each mouse in group A was given full diet,while in group B was given high fat diet.After 20 weeks,all mice were killed and before that,we remained urinary volume of 24 hours.We got blood in inferior caval vein on sterile condition. After we got both kidneys,100mg renal cortex of right kidey was made into nephridial tissue homogenate,while in left kidey,part of cortex was fixed by neutral- formaldehyde to get ready for HE dyeing.These indexes were observed respectively:
1.Body weight and length were obtained to get index of Lee and left renal index(left kidney weight/body weight);
2.The content of cholesterol total(TCH)、triglyceride(TG)、low density lipoprotein cholesterol(LDL-C)、high density lipoprotein cholesterol(HDL-C)、creatinine(Scr)、urea nitrogen(BUN)and blood glucose (Glu)were detected.
3.By urine creatinine(Ucr)and urine protein(UPE)quantitation in 24 hours,creatinine clearance was calculated(to represent glomerular filtration rate, GFR).
4.In both groups,nitric oxide(NO)content in blood、nephridial tissue and urinary nitrite+nitrate excretion(UNOxV)were acquired by nitrate disoxidation method.
5.After left renal cortex was imbedded by paraffin and dyed by HE, histomorphology examination of kidney by optical microscope,glomerulum section area was determined by image analysator.
Results:
1.In obesity group,the level of index of Lee and left renal index was higher significantly(P＜0.01).
2.In obesity group,cholesterol total(TCH),triglyceride(TG)and low density lipoprotein cholesterol(LDL-C)was higher significantly(P＜0.01);high density lipoprotein cholesterol(HDL-C)was lower obviously(P＜0.01);blood glucose higher,but not significant(P＞0.05).
3.In obesity group,urine protein quantitation in 24 hours was higher in group B than group A obviously(P＜0.01);while creatinine clearance(Ccr) higher(P＜0.01).
4.In obesity group,nitric oxide(NO)content in blood、nephridial tissue was lower than group A evidently(P＜0.01);And urinary nitrite+nitrate excretion(UNOxV)was also lower in group B(P＜0.01).
5.In group B,there were evident intercapillary cellular proliferation, sacculus proprius adhesion、stegnosis,interstitial arteriole hyperplasia endothelialis,hyaline degeneration and glomerulum average section area increasing obviously(P＜0.01).
Conclusions:
1.In obesity group,the advancement of Lee index showed obesity model successful.
2.In obesity group,TCH,TG,LDL-C increasing and HDL-C lowering showed conspicuous lipid metabolism disorder.
3.In obesity group,there was obvious loss of nitric oxide(NO)in blood、nephridial tissue and urinary nitrite+nitrate excretion(UNOxV)which can tell us that NO' synthesis insufficient,blood vessel endothelium and capillary vessel endothelium functional disturbance.
4.In obesity group,the phenomenon that urine protein quantitation in 24 hours higher、creatinine clearance(Ccr)higher、glomerulum hypertrophy、evident intercapillary cellular proliferation,sacculus proprius adhesion、stegnosis,interstitial arteriole hyperplasia endothelialis,hyaline degeneration prompted kidney damage.
5.According to correlation analytic result,we can get NO may be closely relevant to obesity-related glomerulonephropathy.
引文
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18 陈慧梅,刘志红.肥胖相关性肾病的发病机制[J].肾脏病与透析肾移植杂志,2005;14(3):268-271.
19 高凌云,何作云,牟娇.氧化修饰低密度脂蛋白对内皮细胞功能的影响[J].中国微循环,2006;10(6):399-401.
20.Christian K,Roberts,R.James Barnard,Ram K.Sindhu,et al.A high-fat,refind-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant inbalance and depresses NOS protein expression[J].J Apple Physiol,98:203-210,2005.
21 Katusic ZS.Vanhoutte PM.Superoxide anion is an endothelium-derived contracting factor[J].Am J Physiol,1989;257(1Pt2):33-37.
22 刘正娟,金宏英,王玉川,等.单纯性肥胖儿童治疗前后尿中微量蛋白变化的观察[J].中国实用儿科杂志,1999,14(8):490-491.
23 Praga M,Hernandez E,Morales E et al.Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis.Nephrol Dial Transplant,2001,16:1790.
24 王庆文.肥胖相关性肾病的临床表现[J].肾脏病与透析肾移植杂志,2005,14(4):343-344.
25 Li Z,Rodriguez-Iturbe B,Ni Z,et al.Effect of hereditary obesity on renal expressions of NO synthase,caveolin- 1,Akt,guanylate cyclase,and calmodulin[J].Kidney Int.2005;68(6)2766-72.
26 A.Erdely,G.Freshour,D.A.Maddox et al.Renal disease in rats with Type 2diabetes is associated with decreased renal nitric oxide production[J].Diabetoloqia.2004;47(10):1672-6.
27 王东红,徐学明.一氧化氮与肾小球硬化[J].国外医学 泌尿系统分册,1998;18(1):6-8。
28 Chagnac A,Weinstein T,Korzets A et al.Glomerular hemodynamics in severe obesity.AM J Physiol Renal Physiol,2000,278:F817.
29 Henegar JR,Bigler SA,Henegar LK et al.Functional and structural changes in the kidney in the early stages of obesity.J AM Soc Nephrol,2001,12:1211.
30 刘志红,黄燕飞.胰岛素抵抗与糖尿病肾病[J].肾脏病与透析肾移植杂志,2002,11:164.
31 Trachtman H,Futterweit S,SinghalP.Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells[J].Biochem Biophys Res Common,1995;207(1):120-125.
32 Kone BC.Nitric oxide in renal health and disease[J].Am J Kidney Dis.1997;30(3):311-313.
33 Trachtman H,Futterweit S,Garg P,et al.Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured,rat mesangial cells[J].Biochem Biophys Res Common.1996;218(3):704-708.
1 Kone BC.Nitric oxide in renal health and disease[J].Am J Kidney Dis.1997;30(3):311-313.
2 Nathan C.Nitric oxide as a secretory product of mammallan cells[J].FASEB J.1992;6(12):3051-3064.
3 Woltz M,Schmetteret L,Ferher W,et al.Effect of nitric oxide synthase inhibition on renal hemodynamics in humans:trbrtdsl by L-arginine[J].Am J Physiol,1997;272(2pt2):178-182.
4 雷定和,尹友生.一氧化氮及其合成酶与肾脏的关系[J].实用临床医学,2004;5(1):123-125.
5 何威逊,方林钧.儿童肥胖相关肾病[J].实用儿科临床杂志,2004;19(1):77-78.
6 单晓益,米杰,王友发.儿童肥胖的流行趋势及其危险因素[J].中国实用儿科杂志,2004;19(3):180-182.
7 易著文.实用小儿.肾脏病手册[M].北京:人民卫生出版社,2005:449-453.
8 陈惠萍,朱茂艳,张波.肥胖相关肾病[J].肾脏病与透析肾移植杂志,2002;11(3):291.
9 Kambham N,Markowitz GS,Valeri AM,et al.Obesity-related glomerulopathy:An emerging epidemic[J].Kidney Int,2001;59:1498-1509.
10 张建江,易著文,杨华彬.肥胖相关肾病的诊断[J].实用儿科临床杂志,2006;21(5):316-317.
11 Ross R,The pathogenesis of atherosclerosis:a perspective for the 1990s[J].Nature,1993;362:801-809.
12 Oflaz H,Ozbey N,Mantar F,et al.Determination of endothelial function and early atherosclerotic changes in healthy obese woman[J].Diabetes Nutr Metab,2003;16(3):176.
13 Woo KS,Chook P,Yu CW,et al.Overweight in children is associated with arterial endothelial dysfunction and intima-media[J].Int J Obes Relat Metab,2004;28:852-857.
14 Nicoletti G,Giugliano G,Pontillo A,et al.Effect of a multidisciplinary program of weight reduction on endothelial function in obese women[J].J Endocrinol Invest,2003;26(3):RC5.
15 陈瑶,汪翼,李燕等.不同干预方法对实验性肥胖大鼠早期血管内皮功能障碍作用的比较[J].中华儿科杂志,2006;44(8):607-610.
16 杨爽,宋光耀,冯丽.脂肪分布与血清瘦素、一氧化氮、血浆内皮素水平的相关性[J].临床荟萃,2005;20(22):1295-1297.
17 葛倩,邓华聪,易旭,肖世尧.肥胖与内皮损伤的关系及其相关机制分析[J].重庆医学,2006;35(7):627-629.
18 肖伟强,肖志强,李艳萍等.肥胖患儿体内抗氧化剂抗氧化酶和丙二醛的检测及分析[J].中国实用儿科杂志,2006;21(3):182-184.
19 郭锡熔,陈荣华,邓静云等.单纯肥胖儿童动脉粥样硬化形成机制的研究[J].南京医科大学学报,1996;16(4):351-353.
20 Katusic ZS.Vanhoutte PM.Superoxide anion is an endothelium-derived contracting factor[J].Am J Physiol,1989;257(1Pt2):33-37.
21 Christian K,Roberts,R.James Barnard,Ram K.Sindhu,et al.A high-fat,refind-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant inbalance and depresses NOS protein expression[J].J Apple Physiol,98:203-210,2005.
22 Ebenbichler CF,Laimer M,Kaser S,et al.Relationship between cholesteryl ester transfer protein and atherogenic lipoprotein profile in morbidly obese women[J].Arterioscler Thromb Vasc Biol,2002;22:1465-1469.
23 Nofer JR,van der Ciet M,Tolle M,et al.HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor SIP3.J Clin Invest,2004;113:569-581.
24 孔宏亮,齐国先,姚宇等.低高密度脂蛋白胆固醇血症患者血浆一氧化氮合酶和一氧化氮水平相关性研究[J].中国循环杂志,2006;21(3):198-201.
25 周曙明,丘惠娴,邱小丽.单纯性肥胖症儿童运动训练前后血管内皮分泌 功能及氧化低密度脂蛋白的变化[J].中国物理医学与康复杂志,2003;25(5):273-274.
26 王转锁,李凤良,宋钦华.一氧化氮与糖尿病肾病的研究[J].医学综述,2004;10(9):560-562.
27 王东红,徐学明.一氧化氮与肾小球硬化[J].国外医学 泌尿系统分册,1998;18(1):6-8.
28 唐玉琼,何小解.内皮素与一氧化氮对肾病大鼠系膜细胞增生的影响[J].中国现代医学杂志,2002;12(19):12-15.
2 单晓益,米杰,王友发.儿童肥胖的流行趋势及其危险因素[J].中国实用儿科杂志,2004;19(3):180-182.
3 易著文.实用小儿肾脏病手册[M].北京:人民卫生出版社,2005:449-453.
4 Kambham N,Markowitz GS,Valeri AM,et al.Obesity-related glomerulopathy:An emerging epidemic[J].Kidney Int,2001;59:1498-1509.
5 Cohen AH.Massive obesity and the kidney:Amorphologic and statistical study[J].Am J Pathol,1975,81(1):117-130.
6 杨霁云.小儿肥胖对肾脏的影响[J].实用儿科临床杂志,2007;22(17):1289-1292.
7 Schmidt RJ and Baylis C.Total nitric oxide production is low in patients with chronic renal disease[J].Kidney Int 58:1261-1266,2000.
8 Wagner L,Riggleman A,Erdely A,Couser W,and Baylis C.Reduced nitric oxide synthase activity in rats with chronic renal disease due to glomerulonephritis[J].Kidney Int 62:532-536,2002.
9 梁湘辉,唐红英,徐淑兰等.肾病患者血清中一氧化氮水平的变化及意义[J].中南大学学报(医学版),2004;29(50):610-611.
10 王转锁,李凤良,宋钦华.一氧化氮与糖尿病肾病的研究[J].医学综述,2004;10(9):560-562.
11 葛倩,邓华聪,易旭,肖世尧.肥胖与内皮损伤的关系及其相关机制分析[J].重庆医学,2006;35(7):627-629.
12 Ross R,The pathogenesis of atherosclerosis:a perspective for the 1990s[J].Nature,1993;362:801-809.
13 Oflaz H,Ozbey N,Mantar F,et al.Determination of endothelial function and early atherosclerotic changes in healthy obese woman[J].Diabetes Nutr Metab,2003;16(3):176.
14 任敏,曾智,梁玉佳.低密度脂蛋白和高密度脂蛋白对动脉內皮细胞一氧化氮生成的影响[J].中国动脉硬化杂志,20002
15 Nofer JR,van der Ciet M,Tolle M,et al.HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor SIP3.J Clin Invest,2004;113:569-581.
16 孔宏亮,齐国先,姚宇等.低高密度脂蛋白胆固醇血症患者血浆一氧化氮合酶和一氧化氮水平相关性研究[J].中国循环杂志,2006;21(3):198-201.
17 Ebenbichler CF,Laimer M,Kaser S,et al.Relationship between cholesteryl ester transfer protein and atherogenic lipoprotein profile in morbidly obese women[J].Arterioscler Thromb Vasc Biol,2002;22:1465-1469.
18 陈慧梅,刘志红.肥胖相关性肾病的发病机制[J].肾脏病与透析肾移植杂志,2005;14(3):268-271.
19 高凌云,何作云,牟娇.氧化修饰低密度脂蛋白对内皮细胞功能的影响[J].中国微循环,2006;10(6):399-401.
20.Christian K,Roberts,R.James Barnard,Ram K.Sindhu,et al.A high-fat,refind-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant inbalance and depresses NOS protein expression[J].J Apple Physiol,98:203-210,2005.
21 Katusic ZS.Vanhoutte PM.Superoxide anion is an endothelium-derived contracting factor[J].Am J Physiol,1989;257(1Pt2):33-37.
22 刘正娟,金宏英,王玉川,等.单纯性肥胖儿童治疗前后尿中微量蛋白变化的观察[J].中国实用儿科杂志,1999,14(8):490-491.
23 Praga M,Hernandez E,Morales E et al.Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis.Nephrol Dial Transplant,2001,16:1790.
24 王庆文.肥胖相关性肾病的临床表现[J].肾脏病与透析肾移植杂志,2005,14(4):343-344.
25 Li Z,Rodriguez-Iturbe B,Ni Z,et al.Effect of hereditary obesity on renal expressions of NO synthase,caveolin- 1,Akt,guanylate cyclase,and calmodulin[J].Kidney Int.2005;68(6)2766-72.
26 A.Erdely,G.Freshour,D.A.Maddox et al.Renal disease in rats with Type 2diabetes is associated with decreased renal nitric oxide production[J].Diabetoloqia.2004;47(10):1672-6.
27 王东红,徐学明.一氧化氮与肾小球硬化[J].国外医学 泌尿系统分册,1998;18(1):6-8。
28 Chagnac A,Weinstein T,Korzets A et al.Glomerular hemodynamics in severe obesity.AM J Physiol Renal Physiol,2000,278:F817.
29 Henegar JR,Bigler SA,Henegar LK et al.Functional and structural changes in the kidney in the early stages of obesity.J AM Soc Nephrol,2001,12:1211.
30 刘志红,黄燕飞.胰岛素抵抗与糖尿病肾病[J].肾脏病与透析肾移植杂志,2002,11:164.
31 Trachtman H,Futterweit S,SinghalP.Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells[J].Biochem Biophys Res Common,1995;207(1):120-125.
32 Kone BC.Nitric oxide in renal health and disease[J].Am J Kidney Dis.1997;30(3):311-313.
33 Trachtman H,Futterweit S,Garg P,et al.Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured,rat mesangial cells[J].Biochem Biophys Res Common.1996;218(3):704-708.
1 Kone BC.Nitric oxide in renal health and disease[J].Am J Kidney Dis.1997;30(3):311-313.
2 Nathan C.Nitric oxide as a secretory product of mammallan cells[J].FASEB J.1992;6(12):3051-3064.
3 Woltz M,Schmetteret L,Ferher W,et al.Effect of nitric oxide synthase inhibition on renal hemodynamics in humans:trbrtdsl by L-arginine[J].Am J Physiol,1997;272(2pt2):178-182.
4 雷定和,尹友生.一氧化氮及其合成酶与肾脏的关系[J].实用临床医学,2004;5(1):123-125.
5 何威逊,方林钧.儿童肥胖相关肾病[J].实用儿科临床杂志,2004;19(1):77-78.
6 单晓益,米杰,王友发.儿童肥胖的流行趋势及其危险因素[J].中国实用儿科杂志,2004;19(3):180-182.
7 易著文.实用小儿.肾脏病手册[M].北京:人民卫生出版社,2005:449-453.
8 陈惠萍,朱茂艳,张波.肥胖相关肾病[J].肾脏病与透析肾移植杂志,2002;11(3):291.
9 Kambham N,Markowitz GS,Valeri AM,et al.Obesity-related glomerulopathy:An emerging epidemic[J].Kidney Int,2001;59:1498-1509.
10 张建江,易著文,杨华彬.肥胖相关肾病的诊断[J].实用儿科临床杂志,2006;21(5):316-317.
11 Ross R,The pathogenesis of atherosclerosis:a perspective for the 1990s[J].Nature,1993;362:801-809.
12 Oflaz H,Ozbey N,Mantar F,et al.Determination of endothelial function and early atherosclerotic changes in healthy obese woman[J].Diabetes Nutr Metab,2003;16(3):176.
13 Woo KS,Chook P,Yu CW,et al.Overweight in children is associated with arterial endothelial dysfunction and intima-media[J].Int J Obes Relat Metab,2004;28:852-857.
14 Nicoletti G,Giugliano G,Pontillo A,et al.Effect of a multidisciplinary program of weight reduction on endothelial function in obese women[J].J Endocrinol Invest,2003;26(3):RC5.
15 陈瑶,汪翼,李燕等.不同干预方法对实验性肥胖大鼠早期血管内皮功能障碍作用的比较[J].中华儿科杂志,2006;44(8):607-610.
16 杨爽,宋光耀,冯丽.脂肪分布与血清瘦素、一氧化氮、血浆内皮素水平的相关性[J].临床荟萃,2005;20(22):1295-1297.
17 葛倩,邓华聪,易旭,肖世尧.肥胖与内皮损伤的关系及其相关机制分析[J].重庆医学,2006;35(7):627-629.
18 肖伟强,肖志强,李艳萍等.肥胖患儿体内抗氧化剂抗氧化酶和丙二醛的检测及分析[J].中国实用儿科杂志,2006;21(3):182-184.
19 郭锡熔,陈荣华,邓静云等.单纯肥胖儿童动脉粥样硬化形成机制的研究[J].南京医科大学学报,1996;16(4):351-353.
20 Katusic ZS.Vanhoutte PM.Superoxide anion is an endothelium-derived contracting factor[J].Am J Physiol,1989;257(1Pt2):33-37.
21 Christian K,Roberts,R.James Barnard,Ram K.Sindhu,et al.A high-fat,refind-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant inbalance and depresses NOS protein expression[J].J Apple Physiol,98:203-210,2005.
22 Ebenbichler CF,Laimer M,Kaser S,et al.Relationship between cholesteryl ester transfer protein and atherogenic lipoprotein profile in morbidly obese women[J].Arterioscler Thromb Vasc Biol,2002;22:1465-1469.
23 Nofer JR,van der Ciet M,Tolle M,et al.HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor SIP3.J Clin Invest,2004;113:569-581.
24 孔宏亮,齐国先,姚宇等.低高密度脂蛋白胆固醇血症患者血浆一氧化氮合酶和一氧化氮水平相关性研究[J].中国循环杂志,2006;21(3):198-201.
25 周曙明,丘惠娴,邱小丽.单纯性肥胖症儿童运动训练前后血管内皮分泌 功能及氧化低密度脂蛋白的变化[J].中国物理医学与康复杂志,2003;25(5):273-274.
26 王转锁,李凤良,宋钦华.一氧化氮与糖尿病肾病的研究[J].医学综述,2004;10(9):560-562.
27 王东红,徐学明.一氧化氮与肾小球硬化[J].国外医学 泌尿系统分册,1998;18(1):6-8.
28 唐玉琼,何小解.内皮素与一氧化氮对肾病大鼠系膜细胞增生的影响[J].中国现代医学杂志,2002;12(19):12-15.