肾素（前体）受体系统致人脐静脉内皮细胞损伤机制的研究
摘要
近年来,人们发现了肾素-血管紧张素系统(renin angitensin system,RAS)中另一活性物质：肾素(前体)受体。目前人们克隆出两种肾素(前体)受体,一种是6-磷酸甘露糖/Ⅱ型胰岛素样生长因子受体(mainnose-6-phosphate/insulin-like growth factor II receptor,M6P/IGF2R),被人们认为在肾素(前体)的清除机制中发挥重要作用。另一种是功能型受体：肾素(前体)受体[(pro)renin receptor, (P)RR]。(P)RR在心肾疾病中的作用越来越受到人们的关注,现已证实其存在于肾系膜细胞、血管平滑肌细胞、肾脏、心脏及大脑等细胞组织中。该受体与肾素(前体)结合后,可以通过不依赖于传统的血管紧张素Ⅱ(Angiotensin-Ⅱ,Ang-Ⅱ)途径,激活细胞内信号转导通路,上调某些基因的表达。丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPKs)是细胞内的一类丝氨酸/苏氨酸蛋白激酶,其存在于大多数细胞内,可将细胞外刺激信号转导至细胞及其核内,并引起细胞生物学反应(如细胞增殖、分化、转化及凋亡等),哺乳动物细胞中已鉴定的3个主要的MAPK亚族包括：细胞外信号调节蛋白激酶(extracellular signal-regulated kinase 1 and 2,ERK1/2)亚族,p38丝裂原活化蛋白激酶(p38 MAPKs)亚族和c-Jun氨基末端激酶(JNK)亚族,其中细胞外信号调节激酶ERK1/2及p38 MAPKs信号转导通路在炎症和氧化应激中起重要作用。本课题组前期工作已证实(P)RR存在于人脐静脉内皮细胞中(human umbilical vein endothelian cells, HUVECs),而(P)RR在HUVECs中对炎症因子VCAM-1和氧化应激指标SOD的影响及干扰(P)RR表达是否可抑制(P)RR对VCAM-1及SOD的影响尚无报道,(P)RR致炎症反应及氧化应激作用是否与信号通路ERK1/2及P38 MAPKs有联系还不清楚。扰(P)RR后对ERK1/2及p38 MAPKs信号通路蛋白表达、血管细胞间粘附分子(vascular cell adhesion molecule-1,VCAM-1)蛋白表达及超氧化物歧化酶(superoxide dismutase, SOD)浓度的影响,从而探讨其致HUVECs损伤的机制,阐述其与动脉粥样硬化(atherosclerosis, AS)等伴有血管内皮损伤性心血管疾病的关系。
方法：
1.体外培养原代HUVECs,CD34流式细胞鉴定。
2.在HUVECs中以siRNA干扰(P)RR,用RT-PCR方法检测干扰24,48及72小时后(P)RR的mRNA表达,确定干扰效率最佳时间点。
3.以奥美沙坦和PD123319阻断Ang-Ⅱ受体AT1、AT2。分别以人重组肾素(renin)及肾素前体(prorenin)处理HUVECs,于处理后5,10,20,35,60,90分钟收取蛋白,用western blot法检测ERK1/2及p38信号通路蛋白磷酸化程度,确定肾素及其前体刺激致两信号通路蛋白磷酸化的最强时间点。
4.以奥美沙坦和PD123319处理HUVECs30分钟后,分别以人重组肾素及肾素前体刺激HUVECs,分别用western blot法,ELISA法和比色法观察肾素及其前体是否可使信号通路蛋白ERK1/2及p38磷酸化增强、粘附分子VCAM-1表达增高、抗氧化酶SOD含量降低,以及干扰(P)RR表达后是否可阻断或减弱肾素及其前体的上述作用。
结果：
1.CD34流式细胞鉴定,HUVECs百分率达98.35%。
2.RT-PCR结果证实(P)RR的mRNA在HUVECs中有表达,siRNA干扰(P)RR后72小时,(P)RR mRNA在HUVECs中表达最弱。
3.经肾素前体及肾素处理HUVECs后,信号通路蛋白ERK1/2及p38磷酸化水平增强,在肾素作用于细胞后20分钟,ERK及p38磷酸化程度最强；分别在肾素前体作用于细胞后60分钟及35分钟,ERK及p38磷酸化最强。
4.人重组肾素及肾素前体刺激HUVECs,可增高信号通路蛋白ERK1/2及p38磷酸化水平,上调粘附分子VCAM-1表达,降低抗氧化酶SOD含量。干扰(P)RR后上述作用减弱。
结论：
(P)RR存在于HUVECs中。在HUVECs中,肾素及其前体通过(P)RR途径可减少抗氧化酶SOD含量,同时激活ERK1/2及p38MAPKs信号通路,上调炎症因子VCAM-1蛋白表达,从而引起内皮细胞损伤,导致AS等相关疾病的发生。干扰(P)RR表达,可有效抑制以上作用,发挥内皮保护作用,为临床治疗RAS过度激活所致的伴有内皮损伤的疾病提供新的理论依据。
In recent years, it has been proved that (pro)rennin receptor((P)RR)is a new active substance in renin angitensin system(RAS). Two types of (pro)renin receptor have been cloned until date, one is mainnose-6-phosphate/insulin-like growth factorⅡreceptor(M6P/IGF2R) which thought to be involved in the clear mechanisms of (pro)renin, the other is the functional receptor (P)RR. Nowsdays, more and more attention has been paid to (P)RR in the heart and kidney disease. It was confirmed that (P)RR exists in the renal mesangial cells, vascular smooth muscle cells, kidney, heart, brain and other cells and tissues. (Pro)renin receptor-bound prorenin and renin activates the intracellular signaling pathways independent of the generated angiotensinⅡ(Ang-Ⅱ), up-regulate of genes expression. Mitogen-activated protein kinases (MAPKs) are serien/ threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as cell proliferation, differentiation, transformation and apoptosis. MAPKs family include extracellular signal regulated kinase (ERK), stress-activated c-Jun N-terminal kinase (JNK/ SAPK), and p38/RK/CSBP protein kinase. Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAPKs are two of MAPKs which play an important role in inflammation and oxidative stress. Our group has found that (P)RR existes in the human umbilical vein endothelian cells(HUVECs) by immunohistochemistry. but it was not yet reported the effect about (P)RR on inflammatory factors VCAM-1 expression and oxidative stress on HUVECs and whether interference (P)RR could inhibited these effects. It was not clear whether inflammation and oxidative stress induced by (P)RR were relatived to signaling pathway ERK 1/2 and p38 MAPKs.
Objectives:To investigate whether (pro)renin can activate the (P)RR leading to the phosphorylation of ERK and p38 MAPK singaling pathway and increase the expression of VCAM-1 and reduce the activity of SOD. Thus to study the mechanism about (P)RR on endothelial damage, explain the relationship between (P)RR and cardiovascular disease such as atherosclerosis(AS).
Methods:
1.HUVECs were cultured in vitro, indentified by CD34 Flow Cytometry
2.HUVECs were incubated with (P)RR siRNA respectively 24,48 and 72 hours, the mRNA of (P)RR expression was detected by RT-PCR.
3.To determine the (pro)renin stimulation time on HUVECs, ERK1/2 and p38 pathway protein phosphorylation were checked by western blot when 5,10,20,35,60,90 minutes after treatment with (pro)renin on HUVECs. Ang-Ⅱreceptor AT1 and AT2 were blocked by Olmesartan and PD123319.
4.Ang-Ⅱreceptor AT1 and AT2 were blocked by Olmesartan and PD123319. Western blot was used to detected whether signaling pathway ERK1/2 and p38 were phosphorylated, ELISA was used to checked whether vascular cell adhesion molecule VCAM-1 expression was increased and Colorimetry was used to detected whether antioxidant SOD activity was reduced, and whether all these reactions were inhibited after (P)RR was interferenced.
Results:
1.98.35% HUVECs were identificated by CD34 Flow Cytometry.
2.The weakest expression of (P)RR mRNA was at the point of 72 hours after interfered with (P)RR-specific siRNA.
3.In HUVECs, ERK 1/2 and p38 MAPKs protein were significantly phosphorylated after stimulated with (pro)renin, which were time dependent.
4.ERK and p38 MAPKs singaling pathways were provoked and the expression of VCAM-1 was increased and the activity of SOD was decreased by (pro)renin, while interfered (P)RR could inhibite these reactions.
Conclusion:
(P)RR expresses on HUVECs. Prorenin and renin can activate the (P)RR, lead to oxidative stress and increase phosphorylation of ERK and p38 MAPKs protein and increase the expression of VCAM-1 by independent Ang-Ⅱway. Thus lead to endothelial damage disease. But all these effects can be inhibited by interfering (P)RR. So interfere (P)RR play a role in endothelium protection. A new evidence was provided in clinical treament about endothelial damage disease.
方法：
1.体外培养原代HUVECs,CD34流式细胞鉴定。
2.在HUVECs中以siRNA干扰(P)RR,用RT-PCR方法检测干扰24,48及72小时后(P)RR的mRNA表达,确定干扰效率最佳时间点。
3.以奥美沙坦和PD123319阻断Ang-Ⅱ受体AT1、AT2。分别以人重组肾素(renin)及肾素前体(prorenin)处理HUVECs,于处理后5,10,20,35,60,90分钟收取蛋白,用western blot法检测ERK1/2及p38信号通路蛋白磷酸化程度,确定肾素及其前体刺激致两信号通路蛋白磷酸化的最强时间点。
4.以奥美沙坦和PD123319处理HUVECs30分钟后,分别以人重组肾素及肾素前体刺激HUVECs,分别用western blot法,ELISA法和比色法观察肾素及其前体是否可使信号通路蛋白ERK1/2及p38磷酸化增强、粘附分子VCAM-1表达增高、抗氧化酶SOD含量降低,以及干扰(P)RR表达后是否可阻断或减弱肾素及其前体的上述作用。
结果：
1.CD34流式细胞鉴定,HUVECs百分率达98.35%。
2.RT-PCR结果证实(P)RR的mRNA在HUVECs中有表达,siRNA干扰(P)RR后72小时,(P)RR mRNA在HUVECs中表达最弱。
3.经肾素前体及肾素处理HUVECs后,信号通路蛋白ERK1/2及p38磷酸化水平增强,在肾素作用于细胞后20分钟,ERK及p38磷酸化程度最强；分别在肾素前体作用于细胞后60分钟及35分钟,ERK及p38磷酸化最强。
4.人重组肾素及肾素前体刺激HUVECs,可增高信号通路蛋白ERK1/2及p38磷酸化水平,上调粘附分子VCAM-1表达,降低抗氧化酶SOD含量。干扰(P)RR后上述作用减弱。
结论：
(P)RR存在于HUVECs中。在HUVECs中,肾素及其前体通过(P)RR途径可减少抗氧化酶SOD含量,同时激活ERK1/2及p38MAPKs信号通路,上调炎症因子VCAM-1蛋白表达,从而引起内皮细胞损伤,导致AS等相关疾病的发生。干扰(P)RR表达,可有效抑制以上作用,发挥内皮保护作用,为临床治疗RAS过度激活所致的伴有内皮损伤的疾病提供新的理论依据。
In recent years, it has been proved that (pro)rennin receptor((P)RR)is a new active substance in renin angitensin system(RAS). Two types of (pro)renin receptor have been cloned until date, one is mainnose-6-phosphate/insulin-like growth factorⅡreceptor(M6P/IGF2R) which thought to be involved in the clear mechanisms of (pro)renin, the other is the functional receptor (P)RR. Nowsdays, more and more attention has been paid to (P)RR in the heart and kidney disease. It was confirmed that (P)RR exists in the renal mesangial cells, vascular smooth muscle cells, kidney, heart, brain and other cells and tissues. (Pro)renin receptor-bound prorenin and renin activates the intracellular signaling pathways independent of the generated angiotensinⅡ(Ang-Ⅱ), up-regulate of genes expression. Mitogen-activated protein kinases (MAPKs) are serien/ threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as cell proliferation, differentiation, transformation and apoptosis. MAPKs family include extracellular signal regulated kinase (ERK), stress-activated c-Jun N-terminal kinase (JNK/ SAPK), and p38/RK/CSBP protein kinase. Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAPKs are two of MAPKs which play an important role in inflammation and oxidative stress. Our group has found that (P)RR existes in the human umbilical vein endothelian cells(HUVECs) by immunohistochemistry. but it was not yet reported the effect about (P)RR on inflammatory factors VCAM-1 expression and oxidative stress on HUVECs and whether interference (P)RR could inhibited these effects. It was not clear whether inflammation and oxidative stress induced by (P)RR were relatived to signaling pathway ERK 1/2 and p38 MAPKs.
Objectives:To investigate whether (pro)renin can activate the (P)RR leading to the phosphorylation of ERK and p38 MAPK singaling pathway and increase the expression of VCAM-1 and reduce the activity of SOD. Thus to study the mechanism about (P)RR on endothelial damage, explain the relationship between (P)RR and cardiovascular disease such as atherosclerosis(AS).
Methods:
1.HUVECs were cultured in vitro, indentified by CD34 Flow Cytometry
2.HUVECs were incubated with (P)RR siRNA respectively 24,48 and 72 hours, the mRNA of (P)RR expression was detected by RT-PCR.
3.To determine the (pro)renin stimulation time on HUVECs, ERK1/2 and p38 pathway protein phosphorylation were checked by western blot when 5,10,20,35,60,90 minutes after treatment with (pro)renin on HUVECs. Ang-Ⅱreceptor AT1 and AT2 were blocked by Olmesartan and PD123319.
4.Ang-Ⅱreceptor AT1 and AT2 were blocked by Olmesartan and PD123319. Western blot was used to detected whether signaling pathway ERK1/2 and p38 were phosphorylated, ELISA was used to checked whether vascular cell adhesion molecule VCAM-1 expression was increased and Colorimetry was used to detected whether antioxidant SOD activity was reduced, and whether all these reactions were inhibited after (P)RR was interferenced.
Results:
1.98.35% HUVECs were identificated by CD34 Flow Cytometry.
2.The weakest expression of (P)RR mRNA was at the point of 72 hours after interfered with (P)RR-specific siRNA.
3.In HUVECs, ERK 1/2 and p38 MAPKs protein were significantly phosphorylated after stimulated with (pro)renin, which were time dependent.
4.ERK and p38 MAPKs singaling pathways were provoked and the expression of VCAM-1 was increased and the activity of SOD was decreased by (pro)renin, while interfered (P)RR could inhibite these reactions.
Conclusion:
(P)RR expresses on HUVECs. Prorenin and renin can activate the (P)RR, lead to oxidative stress and increase phosphorylation of ERK and p38 MAPKs protein and increase the expression of VCAM-1 by independent Ang-Ⅱway. Thus lead to endothelial damage disease. But all these effects can be inhibited by interfering (P)RR. So interfere (P)RR play a role in endothelium protection. A new evidence was provided in clinical treament about endothelial damage disease.
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54. Carlos Henrique de Castro, Robson Augusto Souza dos Santos, Anderson Jose Ferreira, et al. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 reeepton.in tile mouse heart. Hypertension 2005; 46:937-942.
55. De Mello W C. Angiotensln(1-7) re-establishes impulse conduction in cardiac muscle during ischaemia-reperfusion. The role of the sodium pump. J Renin Angiotensin Aldosterone Syst 2004; 5:203-208.
1. Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 2007;59:251-87.
2. S. Billet, F. Aguilar, C. Baudry, et al. Role of angiotensin Ⅱ AT1 receptor activation in cardiovascular diseases. Kidney Int.2008; 74:1379-1384.
3. Remuzzi, N. Perico, M. Macia, et al. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int 2005; 99:S57-S65.
4. K. Vijayaraghavan, P.C. Deedwania, The renin-angiotensin system as a thera-peutic target to prevent diabetes and its complications. Cardiol. Clin 2005; 23:165-183.
5. Griendling, K.K., T.J. Murphy, et al. Molecular biology of the renin-angiotensin system. Circulationb 1993; 87:1816-1828.
6. Zaid Abassi, Joseph Winaver, Giora Z. Feuerstein. The biochemical pharmaco-logy of renin inhibitors:Implications for translational medicine in hypertension, diabetic nephropathy and heart failure:Expectations and reality. Biochemical Pharmacology 2009; 78:933-940.
7. Hsueh WA, Baxter JD. Human prorenin. Hypertension 1991; 17:469-479.
8. Danser AHJ, Van Den Dorpel MA, Deinum J, et al. Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy. J Clin Endocrinol Metab 1989; 68:160-167.
9. Wilson DM, Luetscher JA. Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N Engl J Med 1990; 323: 1101-1106.
10. Nguyen G, Delarue F, Berrou J, et al. Specific receptor bindingof renin on humanmesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int 1996; 50:1897-1903.
11. Nabi, A.H., A. Kageshima, M.N. Uddin, et al. Binding properties of rat prorenin and renin to the recombinant rat renin/prorenin receptor prepared by a baculo-virus expression system. Int J Mol Medb 2006; 18:483-488.
12. Remuzzi, N. Perico, M. Macia, et al. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int2005; S57-S65.
13. Vijayaraghavan, P.C. Deedwania, The renin-angiotensin system as a therapeutic target to prevent diabetes and its complications. Cardiol Clin 2005;23:165-183.
14. H. Jan Danser, W.W. Batenburg, J.H. van Esch. Prorenin and the (pro)renin receptor-an update. Nephrol. Dial. Transplant.2007; 22:1288-1292.
15. Nguyen. Renin/prorenin receptors. Kidney Int 2006; 69:1503-1506.
16. Nguyen, A. Contrepas. The (pro)renin receptors. J Mol Med 2008; 86:643-646.
17. Nguyen, A.H. Danser. Prorenin and (pro)renin receptor:a review of availabl data from in vitro studies and experimental models in rodents. Exp Physiol 2008; 93:557-563.
18. Khan BV, harrison DG, Olbrych MT, et al. Nitric oxide regulates vascular cell adhension molecular 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 1996; 93: 9114-9119.
19. Zeiher AM, Fisslthaler B, Schray-Utz B, et al. Nitric oxide modulates the expression of monocyte chemotactic protein-1 in cultured human endothelial cells. Circ Res 1995; 76:980-986.
20. Quy N. Diep, MSc Pharm, PhD Mohammed E1 Mabrouk et al. Structure, Endothelial Function, Cell Growth, and Inflammation in Blood Vessels of Angiotensin II-Infused Rats. Circulation 2002; 105:2296-2302.
21. Maki Uraoka, Koji Ikeda, Yusuke Nakagawa et al. Prorenin induces ERK activation in endothelial cells to enhance eovascularization independently of the renin-angiotensin system. Biochemical and Biophysical Research Communi-cations 2009; 390:1202-1207.
22. Nguyen G, Delarue F, Burckle C, et al. Pivotal role of the renin/prorenin receptor in angiotensin Ⅱ production and cellular responses to renin. J Clin Invest 2002; 109:1417-1427.
23. Suzuki, F., M. Hayakawa, T. Nakagawa, et al. Human prorenin has "gate and handle" regions for its non-proteolytic activation. J Biol Chemb 2003; 278: 22217-22222.
24. Burckle CA, Jan Danser AH, Muller DN, et al. Elevated blood pressure and heart rate in human renin receptor transgenic rats.Hypertension 2006; 47:552-556.
25. Atsuhiro Ichihara,Yuki Kaneshiro,Tomoko Takemitsu, et al. Contribution of Nonproteolytically Activated Prorenin in Glomeruli to Hypertensive Renal Damage. J Am Soc Nephrol 2006; 17:2495-2503.
26. Burckle CA, Danser AHJ, Muller DN, et al. Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension 2006; 47:552-556.
27. Oscar Alcazar a, Scott W. Cousins b, Gary E. Striker et al. (Pro)renin receptor is expressed in human retinal pigment epithelium and participates in extracellular matrix remodeling. Experimental Eye Research 2009; 89:638-647.
28. Amsterdam A, Nissen RM, Sun Z, et al. Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA 2004; 101:12792-12797.
29. Ramser J, Abidi FE, Burckle CA,er al. A unique exonic splice enhancer mtation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet 2005; 14:1019-1027.
30. Kemp TJ, Sadusky TJ, Saltisi F, et al. Identification ofA nkrd2, anovel skaletalmusch gene codiIlg for a stretch-responsive ankmn-repeat pmtmn. Genomics 2000; 66:229-241.
31. Yung HH, Jin JC, Nen CC, et al. Role of reactive oxygen species-sensitive extracellular signal regulated kinase pathway in angiotensin II induced endothelin gene expression in vacular endothellal cells. J Vasc Res 2004; 41: 64-74.
32. Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal 1997; 9:337-351.
33. Taniyama Y, Ushio-Fukai M, Hitomi H, et al. Role of p38 MAPK and MAPKAPK-2 in angiotensin Ⅱ-induced Akt activation in vascular smooth muscle cells. Am J Physiol Cell Physiol 2004; 287:C494-C499.
34. Huang Y, Wongamorntham S, Kasting J, et al. Renin increases mesangial cell transforming growth factor-betal and matrix proteins through receptor mediated, angiotensin Ⅱ-independent mechanisms. Kidney Int 2006; 69:105-113.
35. Saris, J.J., P.A. t Hoen, I.M. Garrelds, et al. Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. Hypertension 2006; 48:564-571.
36. Ichihara A, Suzuki F, Nakagawa T. Prorenin receptor blockade inhibits development of golmerulosclerosis in diabetic angiotensin II type la receptor-deficient mice. J Am Soc Nephrol 2006; 17:1950-1961.
37. Oscar Alcazar a, Scott W. Cousins b, Gary E. Striker et al. (Pro)renin receptor is expressed in human retinal pigment epithelium and participates in extracellular matrix remodeling. Experimental Eye Research 2009; 89:638-647.
38. Rueckschloss U, Quinn MT, Holtz, et al. Dose-dependent regulation of NAD(P)H oxidase expression by angiontensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002; 22:1845-1851.
39. Warnholtz A, Nickenig G, Schulz E, et al. Increased NADH-oxidase mediated superoxide production in the earhy stages of arteriosclerosis evidence of involvement of the renin angiotensin system.. Circulation 1999;99:2027-2033.
40. DeGraba TJ, Penix L, McCarron RM, et al. Increased endothelial expression of intercellular adhesion molecule-1 in symptimatic versus asymptomatic human carotid atherosclerotic plaque. Stroke 1998; 29:1405-1410
41. Jang Y, Lincoff M, Plow EF, et al. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 1994; 24:1591-1601.
2. Kawano H, Do YS, Kawano Y, et al. AngiotensinⅡhas multiple profibrotiec effects in Human cardaic fibroblasts. Circulation 2000; 101:1130-1137.
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6. Yan C, Kim D, Aizawa T, et al. Functional interplay between angiotensin Ⅱ and nitric oxide:cyclic GMP as a key mediator. Arterioscler Thromb Vasc Biol 2003; 23:26-36,.
7. Yung HH, Jin JC, Nen CC, et al. Role of reactive oxygen species-sensitive extracellular signal regulated kinase pathway in angiotensin Ⅱ induced endothelin gene expression in vacular endothellal cells. J Vasc Res 2004; 41: 64-74.
8. Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal 1997; 9:337-351.
9. Taniyama Y, Ushio-Fukai M, Hitomi H, et al. Role of p38 MAPK and MAPKAPK-2 in angiotensin Ⅱ-induced Akt activation in vascular smooth muscle cells. Am J Physiol Cell Physiol 2004; 287:C494-C499.
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13. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase:role in cardiovascular biology and disease. Circ Res 2000; 86:494-501.
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15. Natarajan R, Scott S, Bai W, et al. Angiotensin II signaling in vascular smooth muscle cells under high glucose conditions. Hypertension 1999; 33:378-384.
16. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995; 273:1450-1456.
17. Igarashi M, Hirata A, Yamaguchi H, et al. Candesartan inhibits carotid intimal thickening and ameliorates insulin resistance in balloon-injured diabetic rats. Hypertension 2001; 38:1255-1259.
18. Marrero MB, Venema VJ, Ju H, et al. Regulation of angiotensin Ⅱ-induced JAK2 tyrosine phosphorylation:roles of SHP-1 and SHP-2. Am J Physiol Cell Physiol 1998; 275:C1216-C1223,.
19. Franz IW, Tonnesmann U, Muller JF. Time course of complete normalization of left ventricular hypertrophy during long-time antihypertensive therpy angioten-sion converting enzyme inhibitors. Am J Hypertens 1998; 11:631-639.
20. Keidar S, Attias J, Smith J, et al. The angiotensin-Ⅱ receptor antagonist, losartan, inhibits LDL lipid peroxidation and atherosclerosis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun 1997; 236:622-625.
21. Gaedeke J, PetersH, Noble NA, et al. Angiotensin II,TGF-βand renalfibrosis. Contrib Nephrol 2001; 135:153-160.
22. Praddaude F, Cousins SW, Pecher C, et al. Angiotensin Ⅱ-induced hypertension regulates AT1 receptor subtypes and extracellular matrix turnover in mouse retinal pigment epithelium. Experimental Eye Research 2009; 89:109-118.
23. Ogihara T, Asano T, Ando K, et al. Angiotensin Ⅱ-induced insulin resistance is associated with enhanced insulin signaling. Hypertension 2002; 40:872-879.
24. Ambuhl P, Felix D, Khosla MC. [7-D-ALA]-angiotensin-(1-7):selective antagonism of angiotensin-(1-7) in the rat paraventricular nucleus. Brain Res Bull 1994; 35:289-291.
25. Mariela M, Gironacci, Maria S, et al. Angiotensin-(1-7) Inhibitory Mechanism of Norepinephrine Release in Hypertensive Rats. Hypertension 2004; 44:783-787.
26.钟健,祝之明,杨永健.血管紧张素-(1-7)对大鼠血管平滑肌细胞PKC和ERK1/2的抑制作用.生理学报2001;53:361-363.
27. Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function 1-J-I. Nature 2002; 417:822-828.
28. Tallant E A, Ferrario C M, Gallagher P E. Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol 2005; 289:1560-1566.
29. Ferreira AJ, Jacoby BA, Araujo CA, et al. The nonpeptide angiotensin-(1-7) receptor Mas agonist AVE 0991 attenuates heart failure induced by myocardial infarction. Am J Physiol Heart Circ Physiol 2007; 292:H1113-H1119.
30. Iwata M, Cowling R T, Gurantz D, et al. Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibroilc and antitrophic effects. Am J Physiol Heart Circ Physiol 2005,289:H2356-2363.
31. Nguyen G, Delarue F, Burckle C, et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002;109:1417-1427.
32. Luetscher, J.A, F.B. Kraemer, D.M. Wilson, et al. Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications, N Engl J Medb 1985; 312:1412-1427.
33. Van Kesteren CAM, Danser AHJ, Derkx FH, et al. Mannose-6-phosphate receptor mediated internalization and activation of prorenin by cardiac cells. Hyper-tension 1997; 30:1389-1396.
34. Saris, J.J., P.A. t Hoen, I.M. Garrelds, et al. Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin Ⅱ. Hypertension 2006; 48:564-571.
35. Huang, Y., S. Wongamorntham, J. Kasting, et al. Renin increases mesangial cell transforming growth factor-betal and matrix proteins through receptor-mediated, angiotensin Ⅱ-independent mechanisms.Kidney Intb 2006; 69:105-113.
36. Huang, Y., W.A. Border, and N.A. Noble. Functional renin receptors in renal mesangial cells. Curr Hypertens Repb 2007; 9:133-139.
37. Huang, Y., N.A. Noble, J. Zhang, et al.Renin-stimulated TGF-betal expression is regulated by a mitogen-activated protein kinase in mesangial cells.Kidney Intb 2007; 72:45-52.
38. Feldt S., U. Maschke, R. Dechend, et al. The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling, J Am Soc Nephrolb 2008; 19:743-748.
39. Sakoda M., A. Ichihara, Y. Kaneshiro, et al. (Pro)renin receptor-mediated
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40. Maki Uraoka, Koji Ikeda, Yusuke Nakagawa, et al. Prorenin induces ERK activation in endothelial cells to enhance eovascularization independently of the renin-angiotensin system. Biochemical and Biophysical Research Communi-cations 2009; 390:1202-1207.
41. Takuo Hirose a, Nobuyoshi Mori b, Kazuhito Totsune. Gene expression of (pro)renin receptor is upregulated in hearts and kidneys of rats with congestive heart failure. Peptides 2009; 30:2316-2322.
42. Burckle C.A., Jan Danser A.H., Muller D.N., et al. Elevated blood pressure and heart rate in human renin receptor transgenic rats.Hypertension 2006; 47: 552-556.
43. Atsuhiro Ichihara,Yuki Kaneshiro,Tomoko Takemitsu et al. Contribution of Nonproteolytically Activated Prorenin in Glomeruli to Hypertensive Renal Damage. J Am Soc Nephrol 2006; 17:2495-2503.
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45. Yuki Kaneshiro, Atsuhiro Ichihara, Mariyo Sakoda et al. Slowly progressive, angiotensin Ⅱ-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. American Society of Nephrology 2007; 18:1789-1795.
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50. Border WA, Noble NA. Interaction of transforming growth factor-beta and angiotensin Ⅱ in renal fibrosis. Hypertension1998; 31:181-188.
51. E Ann Tallant, Carlos M, Ferrario, et al. Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor. Physiol Heart Circ Physiol 2005; 289:1560-1566.
52. Z Su, Zimpelmann, K D Burns. Angiotensin-(1-7) inhibits angiotensin-Ⅱ stimulated phosphorylation of MAP kinases in proximal tubular cells. Kidney International 2006; 69:2212-2218.
53. Walkyria Oliveira Sampaio, Robson Augusto Souza dos Santos, Raphael Faria-Silva, et al. Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways. Hypertension 2007; 49:185-192.
54. Carlos Henrique de Castro, Robson Augusto Souza dos Santos, Anderson Jose Ferreira, et al. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 reeepton.in tile mouse heart. Hypertension 2005; 46:937-942.
55. De Mello W C. Angiotensln(1-7) re-establishes impulse conduction in cardiac muscle during ischaemia-reperfusion. The role of the sodium pump. J Renin Angiotensin Aldosterone Syst 2004; 5:203-208.
1. Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 2007;59:251-87.
2. S. Billet, F. Aguilar, C. Baudry, et al. Role of angiotensin Ⅱ AT1 receptor activation in cardiovascular diseases. Kidney Int.2008; 74:1379-1384.
3. Remuzzi, N. Perico, M. Macia, et al. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int 2005; 99:S57-S65.
4. K. Vijayaraghavan, P.C. Deedwania, The renin-angiotensin system as a thera-peutic target to prevent diabetes and its complications. Cardiol. Clin 2005; 23:165-183.
5. Griendling, K.K., T.J. Murphy, et al. Molecular biology of the renin-angiotensin system. Circulationb 1993; 87:1816-1828.
6. Zaid Abassi, Joseph Winaver, Giora Z. Feuerstein. The biochemical pharmaco-logy of renin inhibitors:Implications for translational medicine in hypertension, diabetic nephropathy and heart failure:Expectations and reality. Biochemical Pharmacology 2009; 78:933-940.
7. Hsueh WA, Baxter JD. Human prorenin. Hypertension 1991; 17:469-479.
8. Danser AHJ, Van Den Dorpel MA, Deinum J, et al. Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy. J Clin Endocrinol Metab 1989; 68:160-167.
9. Wilson DM, Luetscher JA. Plasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N Engl J Med 1990; 323: 1101-1106.
10. Nguyen G, Delarue F, Berrou J, et al. Specific receptor bindingof renin on humanmesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int 1996; 50:1897-1903.
11. Nabi, A.H., A. Kageshima, M.N. Uddin, et al. Binding properties of rat prorenin and renin to the recombinant rat renin/prorenin receptor prepared by a baculo-virus expression system. Int J Mol Medb 2006; 18:483-488.
12. Remuzzi, N. Perico, M. Macia, et al. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int2005; S57-S65.
13. Vijayaraghavan, P.C. Deedwania, The renin-angiotensin system as a therapeutic target to prevent diabetes and its complications. Cardiol Clin 2005;23:165-183.
14. H. Jan Danser, W.W. Batenburg, J.H. van Esch. Prorenin and the (pro)renin receptor-an update. Nephrol. Dial. Transplant.2007; 22:1288-1292.
15. Nguyen. Renin/prorenin receptors. Kidney Int 2006; 69:1503-1506.
16. Nguyen, A. Contrepas. The (pro)renin receptors. J Mol Med 2008; 86:643-646.
17. Nguyen, A.H. Danser. Prorenin and (pro)renin receptor:a review of availabl data from in vitro studies and experimental models in rodents. Exp Physiol 2008; 93:557-563.
18. Khan BV, harrison DG, Olbrych MT, et al. Nitric oxide regulates vascular cell adhension molecular 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 1996; 93: 9114-9119.
19. Zeiher AM, Fisslthaler B, Schray-Utz B, et al. Nitric oxide modulates the expression of monocyte chemotactic protein-1 in cultured human endothelial cells. Circ Res 1995; 76:980-986.
20. Quy N. Diep, MSc Pharm, PhD Mohammed E1 Mabrouk et al. Structure, Endothelial Function, Cell Growth, and Inflammation in Blood Vessels of Angiotensin II-Infused Rats. Circulation 2002; 105:2296-2302.
21. Maki Uraoka, Koji Ikeda, Yusuke Nakagawa et al. Prorenin induces ERK activation in endothelial cells to enhance eovascularization independently of the renin-angiotensin system. Biochemical and Biophysical Research Communi-cations 2009; 390:1202-1207.
22. Nguyen G, Delarue F, Burckle C, et al. Pivotal role of the renin/prorenin receptor in angiotensin Ⅱ production and cellular responses to renin. J Clin Invest 2002; 109:1417-1427.
23. Suzuki, F., M. Hayakawa, T. Nakagawa, et al. Human prorenin has "gate and handle" regions for its non-proteolytic activation. J Biol Chemb 2003; 278: 22217-22222.
24. Burckle CA, Jan Danser AH, Muller DN, et al. Elevated blood pressure and heart rate in human renin receptor transgenic rats.Hypertension 2006; 47:552-556.
25. Atsuhiro Ichihara,Yuki Kaneshiro,Tomoko Takemitsu, et al. Contribution of Nonproteolytically Activated Prorenin in Glomeruli to Hypertensive Renal Damage. J Am Soc Nephrol 2006; 17:2495-2503.
26. Burckle CA, Danser AHJ, Muller DN, et al. Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension 2006; 47:552-556.
27. Oscar Alcazar a, Scott W. Cousins b, Gary E. Striker et al. (Pro)renin receptor is expressed in human retinal pigment epithelium and participates in extracellular matrix remodeling. Experimental Eye Research 2009; 89:638-647.
28. Amsterdam A, Nissen RM, Sun Z, et al. Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA 2004; 101:12792-12797.
29. Ramser J, Abidi FE, Burckle CA,er al. A unique exonic splice enhancer mtation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet 2005; 14:1019-1027.
30. Kemp TJ, Sadusky TJ, Saltisi F, et al. Identification ofA nkrd2, anovel skaletalmusch gene codiIlg for a stretch-responsive ankmn-repeat pmtmn. Genomics 2000; 66:229-241.
31. Yung HH, Jin JC, Nen CC, et al. Role of reactive oxygen species-sensitive extracellular signal regulated kinase pathway in angiotensin II induced endothelin gene expression in vacular endothellal cells. J Vasc Res 2004; 41: 64-74.
32. Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal 1997; 9:337-351.
33. Taniyama Y, Ushio-Fukai M, Hitomi H, et al. Role of p38 MAPK and MAPKAPK-2 in angiotensin Ⅱ-induced Akt activation in vascular smooth muscle cells. Am J Physiol Cell Physiol 2004; 287:C494-C499.
34. Huang Y, Wongamorntham S, Kasting J, et al. Renin increases mesangial cell transforming growth factor-betal and matrix proteins through receptor mediated, angiotensin Ⅱ-independent mechanisms. Kidney Int 2006; 69:105-113.
35. Saris, J.J., P.A. t Hoen, I.M. Garrelds, et al. Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. Hypertension 2006; 48:564-571.
36. Ichihara A, Suzuki F, Nakagawa T. Prorenin receptor blockade inhibits development of golmerulosclerosis in diabetic angiotensin II type la receptor-deficient mice. J Am Soc Nephrol 2006; 17:1950-1961.
37. Oscar Alcazar a, Scott W. Cousins b, Gary E. Striker et al. (Pro)renin receptor is expressed in human retinal pigment epithelium and participates in extracellular matrix remodeling. Experimental Eye Research 2009; 89:638-647.
38. Rueckschloss U, Quinn MT, Holtz, et al. Dose-dependent regulation of NAD(P)H oxidase expression by angiontensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002; 22:1845-1851.
39. Warnholtz A, Nickenig G, Schulz E, et al. Increased NADH-oxidase mediated superoxide production in the earhy stages of arteriosclerosis evidence of involvement of the renin angiotensin system.. Circulation 1999;99:2027-2033.
40. DeGraba TJ, Penix L, McCarron RM, et al. Increased endothelial expression of intercellular adhesion molecule-1 in symptimatic versus asymptomatic human carotid atherosclerotic plaque. Stroke 1998; 29:1405-1410
41. Jang Y, Lincoff M, Plow EF, et al. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 1994; 24:1591-1601.