Different role of angiotensin II type 1 and type 2 receptors in renin release by interaction of angiotensin II and renal sympathetic nerve

Background. Angiotensin II (Ang II) is involved in the direct inhibition of renin release from juxtaglomerular (JG) cells in the kidney as the negative feedback loop of the renin-angiotensin system. Ang II also modulates renin release via the sympathetic nervous system, since the renal sympathetic nerves stimulate renin release, and the interaction of the sympathetic nervous system with Ang II has been demonstrated to occur at multiple levels. Methods. Experiments were performed in conscious unrestrained rabbits. Ang II (1.0 ng/kg per min) was infused intravenously for 60 min in renal-denervated (Dx; n = 6) and sham-denervated (Sh; n = 6) rabbits, and plasma renin activity (PRA) was determined. Then the intrarenal administration of the Ang II type-1 receptor (AT1R) antagonist, losartan, or type-2 receptor (AT2R) antagonist, PD123319 was carried out, during infusion of Ang II or saline in both Dx and Sh. Results. PRA was decreased in both Sh (5.9 ± 0.6 to 2.8 ± 0.7 ng/ml per h; n = 6, P < 0.01) and Dx (5.7 ± 0.4 to 3.8 ± 0.6 ng/ml per h; n = 6, P < 0.01) during Ang II infusion. The degree of decrease was significantly less in Dx than in Sh (P < 0.05), indicating that the inhibition of renin release by Ang II is associated with renal nerves. The intrarenal administration of losartan in Sh significantly decreased PRA produced by Ang II (5.6 ± 0.3 to 4.8 ± 0.3 ng/ml per h; n = 6, P < 0.05) vs. saline vehicle (5.7 ± 0.3 to 2.8 ± 0.2 ng/ml per h; n = 6, P < 0.01) (P < 0.05). Blockade with losartan in Dx significantly increased PRA (5.8 ± 0.4 to 6.6 ± 0.4 ng/ml per h; n = 6, P < 0.05) during the infusion of Ang II. Renin response to the Ang II infusion was not influenced by the intrarenal administration of PD123319 alone, in either Sh or Dx. Conclusion. Ang II appears to facilitate sympathetic neurotransmission through the postjunctional AT1R leading to renin release. Received: August 12, 1998 / Accepted: October 9, 1998     

血管紧张素II及其受体在人卵巢的表达

目的　探讨卵巢血管紧张素II(AngII)及其受体 (AT1、AT2 )在人卵巢的表达与分布。　方法　免疫组化法检测33份人卵巢组织标本中AngII及其受体AT1、AT2的表达与分布。　结果　AngII及受体AT1、AT2在卵巢的分布基本一致 ,三者在卵母细胞均有表达 ,大卵泡尤其是排卵前卵泡的颗粒细胞含量丰富 ,卵泡膜细胞几无表达 ;颗粒黄体细胞与膜黄体细胞三者含量均丰富 ,并伴随黄体退化而消失。　结论　AngII及其受体可在人卵巢局部生成 ,并存在于同一种细胞内 ,提示它们可能以自分泌方式参与卵巢功能的调节。     

正常卵巢与多囊卵巢组织血管紧张素II的免疫组化定位

对２０ 例多囊卵巢综合征（ＰＣＯＳ）患者及１２ 例正常育龄妇女的卵巢组织进行血管紧张素ＩＩ的免疫组织化学定位,观察其在卵巢组织的分布情况。结果：正常卵巢组织,卵泡期血管紧张素ＩＩ在卵泡膜细胞为弱阳性染色;颗粒细胞只有近排卵期的优势卵泡呈强阳性反应,并持续至整个黄体期;基质为弱阳性或阴性染色。多囊卵巢组织血管紧张素ＩＩ定位无此波动节律,并以卵泡膜细胞和基质弥漫性强阳性反应为特点。结果提示,血管紧张素ＩＩ参与卵泡发育、排卵、黄体形成和多囊卵巢的病理改变     

1型血管紧张素Ⅱ受体拮抗剂抑制大鼠胰腺纤维化形成

目的探讨1型血管紧张素Ⅱ受体(AT1)拮抗剂洛沙坦对大鼠实验性胰腺纤维化形成的抑制作用。方法胰管内注射2％三硝基苯磺酸(TNBS)诱导大鼠胰腺纤维化模型。于制模后第2天，治疗组给予洛沙坦(10mg／kg体重)灌胃，每日1次，对照组给予等容积的无菌蒸馏水。于制模后3，7，14，21．28d分别处死两组大鼠(每时点各6只)，并留取血清和胰腺组织。通过HE染色和Van Gieson(V-G)染色观察胰腺组织病理学改变和细胞外基质胶原纤维分布。分别应用放射免疫法和酶动力法测定血清透明质酸(HA)和淀粉酶。胰腺组织AT1受体蛋白和mRNA表达分别采用免疫组化和逆转录-聚合酶链式反应(RT-PCR)方法。结果洛沙坦可抑制TNBS诱导的大鼠胰腺纤维化形成，降低胰腺组织炎症细胞浸润、腺泡细胞坏死及纤维化程度，并且能降低血清HA和淀粉酶水平、下调AT1受体基因和蛋白的表达。结论1型血管紧张素Ⅱ受体拮抗剂对TNBS诱导的大鼠胰腺纤维化形成具有抑制作用，表明肾素-血管紧张素系统(RAS)在慢性胰腺炎胰腺纤维化的发生发展过程中起重要的介导调节作用。     

MAPK and angiotensin II receptor in kidney of newborn rats from losartan-treated dams

Several lines of evidence suggest that angiotensin II (A-II) participates in the postnatal development of the kidney in rats. Many effects of A-II are mediated by mitogen-activated protein kinase (MAPK) pathways. This study investigated the influence that treatment with losartan during lactation has on MAPKs and on A-II receptor types 1 (AT(1)) and 2 (AT(2)) expression in the renal cortices of the offspring of dams exposed to losartan during lactation. In addition, we evaluated the relationship between such expression and changes in renal function and structure. Rat pups from dams receiving 2% sucrose or losartan diluted in 2% sucrose (40 mg/dl) during lactation were killed 30 days after birth, and the kidneys were removed for histological, immunohistochemical, and Western blot analysis. AT(1) and AT(2) receptors and p-p38, c-Jun N-terminal kinases (p-JNK) and extracellular signal-regulated protein kinases (p-ERK) expression were evaluated using Western blot analysis. The study-group rats presented an increase in AT(2) receptor and MAPK expression. In addition, these rats also presented lower glomerular filtration rate (GFR), greater albuminuria, and changes in renal structure. In conclusion, newborn rats from dams exposed to losartan during lactation presented changes in renal structure and function, which were associated with AT(2) receptor and MAPK expression in the kidneys.     

Streptococcal erythrogenic toxin B induces apoptosis and proliferation in human leukocytes

BACKGROUND: Previous reports have shown the presence of erythrogenic toxin type B (ETB), apoptosis, proliferation, and leukocyte infiltration in biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). METHODS: Attempting to correlate the apoptotic and proliferative events with the interaction of ETB or its precursor (ETBP) with leukocytes, mononuclear leukocytes from 12 healthy subjects were cultured with ETB or ETBP to analyze the levels of apoptosis, proliferation, expression of modulatory apoptosis gene products, and oxidative metabolism. After four days of incubation, cells were assessed for apoptosis by morphological criteria, annexin V assay, and terminal deoxy transferase uridine triphosphate nick end-labeling (TUNEL) assay. The expression of regulatory apoptosis genes was assessed by relevant monoclonal antibodies; proliferation was by incorporation of radioactive thymidine; and oxidative metabolism was by oxidation of 2',7'-dichlorofuorescein diacetate to 2',7'-dichlorofuorescein. Neutralization of Fas-L and cysteine protease activity of ETB were performed by incubation of ETB-treated leukocyte cultures with anti-human Fas-L mAb or with E64, respectively. RESULTS: Elevated levels of apoptosis in ETBP/ETB-treated leukocytes were found when compared with controls: morphological criteria (P < 0.01), Annexin V (control, 5.01 +/- 0.61; ETBP, 10.60 +/- 1.98%, P = 0.0005), and TUNEL (control, 12.5 +/- 2.6; ETBP, 20.56 +/- 3.06%, P = 0.001; ETB, 30.69 +/- 5.05%, P = 0.001). Increased expression of apoptosis was accompanied by increased expression of Fas (control, 20.15 +/- 5.28; ETBP, 43.51 +/- 5.6%, P = 0.03; ETB, 47.16 +/- 5.54%, P = 0.01), Fas ligand (control, 5.64 +/- 2.38; ETBP, 11.66 +/- 3.65%, P = 0.04; ETB, 16.39 +/- 5.05%, P = 0.02) and p53 products (control, 9.22 +/- 3.44; ETBP, 22.82 +/- 5.72%, P = 0.01; ETB, 24.60 +/- 5.20%, P = 0.01). Treatment of ETB-leukocyte cultures with anti-human Fas-L exhibited 2.2-fold lower apoptosis expression. Treatment with E64 significantly abrogated the apoptotic effect of ETB. There was no increment on leukocyte oxidative metabolism. Mononuclear leukocytes also showed elevated levels of proliferation when treated with different concentrations (from 50 to 6.2 microg/mL) of streptococcal proteins (Stimulation index ranging: ETBP, 5.6 +/- 1.9 to 6.4 +/- 1.9; ETB, 9.9 +/- 2.8 to 13.9 +/- 3.8). CONCLUSIONS: These results delineate an additional pathway for the pathogenesis of APSGN related to the role of cationic streptococcal ETB or ETBP on the induction of apoptosis and proliferation during the course of the disease.     

Streptococcal exotoxin B increases interleukin-6, tumor necrosis factor alpha,interleukin-8 and transforming growth factor beta-1 in leukocytes

Previous reports have shown the presence of streptococcal erythrogenic exotoxin type B (ETB), leukocyte infiltration, interleukin-8 (IL-8), transforming growth factor-beta (TGF-β) and glomerular proliferation in renal biopsies from patients with acute post-streptococcal glomerulonephritis (APSGN). In addition, increased levels of plasma interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), and urinary IL-6, have also been reported in this disease. To determine the effect of streptococcal proteins on leukocyte proliferation and leukocyte production of IL-6, TNFα, IL-8 and TGF-β1, we cultured human mononuclear leukocytes with ETB or ETB precursor (ETBP). After 24 h, 48 h and 96 h, culture supernatants were assessed for cytokines by enzyme-linked immunosorbent assay (ELISA), and for leukocyte proliferation by a monoclonal antibody anti-proliferating cellular nuclear antigen (PCNA). A significant increase in all cytokines was found in ETB- or ETBP-treated cultures when compared with controls. A polyclonal anti-ETB antibody diminished the cytokine stimulatory effect of ETB. An increased number of PCNA-positive cells was observed in ETB or ETBP treated cultures at 48 h and 96 h. Cytokine production and proliferation were not correlated. The stimulatory effect of streptococcal exotoxin B on leukocyte cytokine production may be relevant in renal tissue during the course of APSGN.     

Specific binding of angiotensin II and atrial natriuretic factor in non-nephropathic type I diabetes mellitus

We examined ten patients with type I diabetes mellitus and ten age- and sex-matched healthy controls. Median duration of diabetes was 7 years (range 0.5-24). None of the diabetic patients had hypertension, microalbuminuria, or proliferative retinopathy. Maximal specific binding capacity for angiotensin II to thrombocytes was significantly increased in diabetics (Bmax 11.9 +/- 1.6 sites per cell vs 7.0 +/- 0.9 in controls; P less than 0.01). In contrast, maximal binding for atrial natriuretic factor tended to be lower in type I diabetics (8.84 +/- 1.25 sites per cell vs 16.8 +/- 2.97; P less than 0.07). There was no difference of apparent dissociation constant (KD) for either receptor. Angiotensin II values (RIA) were greater in diabetics (16.2 +/- 1.5 pg/ml vs 8.5 +/- 1.4 in controls; P less than 0.02) and concentrations of atrial natriuretic factor (RIA) were not significantly different. The data suggest increased angiotensin II binding despite high angiotensin II concentrations in non-nephropathic type I diabetic patients. These findings may be relevant when considering the evolution of hypertension and microangiopathy lesions.     

血管紧张素Ⅱ及其受体拮抗剂对肝星状细胞收缩的影响

目的观察血管紧张素Ⅱ及其受体拮抗剂对体外培养的肝星状细胞收缩的影响。方法采用HSC-T6肝星状细胞系作为活化的肝星状细胞的研究模型。将培养的肝星状细胞随机分为对照组、血管紧张素Ⅱ(1×10-9～1×10-5)mol／L组、受体拮抗剂组和血管紧张素Ⅱ+受体拮抗剂组,继续培养48 h后,比较胶原晶格收缩面积的变化,并绘制收缩的量效关系曲线和时效关系曲线。结果血管紧张素Ⅱ各浓度组,胶原晶格的收缩面积比较对照组均明显增加(P<0．05)。随着血管紧张素Ⅱ浓度的升高,胶原晶格的收缩面积逐渐增大,量效曲线呈近似直线的正相关关系;而且随着血管紧张素Ⅱ作用时间的延长,胶原晶格的收缩面积逐渐增大,在48 h之内呈时间依赖性。血管紧张素Ⅱ作用48 h后,胶原晶格面积为(379．337±37．755)mm2,同时加入受体拮抗剂,面积为(540．803±70．018)mm2,胶原晶格的收缩程度比较血管紧张素Ⅱ组明显减轻(P<0．05)。结论血管紧张素Ⅱ能够剂量依赖性和时间依赖性地促进肝星状细胞的收缩,而血管紧张素Ⅱ1型受体拮抗剂能够抑制血管紧张素Ⅱ引起的肝星状细胞的收缩。     

内皮素受体阻断剂对糖尿病大鼠肾脏血管紧张素Ⅱ1型受体表达的影响

目的：观察糖尿病大鼠肾脏血管紧张素Ⅱ1型（AT1）受体的改变以及内皮素受体阻断剂bosentan对其影响。方法：将SD大鼠建成链脲佐菌素诱导的糖尿病模型,设非治疗组、bosentan治疗组和正常对照组。4周后采用免疫组织化学、Western blot及RT－PCR方法检测肾脏AT1受体基因和蛋白表达。结果：与SD对照组相比,糖尿病大鼠存在明显的蛋白尿和内生肌酐清除率升高,其肾脏AngⅡ水平明显升高,同时伴有AT1受体的mRNA和蛋白表达显著下降。bosentan能显著缓解上述异常。结论：糖尿病大鼠肾脏AngⅡ及AT1受体表达明显异常,bosentan具有治疗作用。     

Interaction between adrenomedullin and angiotensin II in DNA synthesis and extracellular matrix accumulation in cultured rat kidney interstitial cells

Background. To investigate the role of adrenomedullin (AM) in the regulation of renal fibrosis, we assessed the effects of AM on angiotensin II (AT II)-induced cell proliferation and extracellular matrix (ECM) accumulation in cultured NRK 49F cells, a cell line derived from normal rat kidney fibroblasts. Methods. Northern blot analysis was performed, using cDNA probes against rat AM, human calcitonin-receptor-like receptor (CRLR), human receptor-activity-modifying protein 2 (RAMP 2), human collagen α-1 (I) (Col-I), human fibronectin (FN), and rat transforming growth factor (TGF)-β1. Polymerase chain reaction (PCR) analysis for CRLR was amplified for 35 cycles. Cell proliferation was determined by the measurement of [³H]thymidine incorporation. Results. We have shown that NRK 49F cells express AM and its receptor, which consists of a CRLR and RAMP 2. Rat AM significantly inhibited cell proliferation and mRNA expression of ECM in the absence and presence of AT II through an AM receptor, because calcitonin gene-related peptide (8-37) [CGRP (8-37)], an antagonist to AM receptor, completely reversed these inhibitory actions. The inhibitory effects appeared to be mediated by a marked increase in intracellular cAMP. While AT II enhanced ECM accumulation by a process depending upon autocrine TGF-β1 secretion in NRK 49F cells, AM suppressed the induction of TGF-β1. Conclusions. The inhibitory action of AM on ECM accumulation may be caused by the suppression of TGF-β1. AM may play an important role in the inhibition of renal interstitial fibrosis under pathological conditions, through acting in an autocrine and/or paracrine fashion. Received: May 2, 2001 / Accepted: November 27, 2001     

Early changes of arginine vasopressin and angiotensin II in patients with acute cerebral injury

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The role of angiotensin II type 1 receptor-activating antibodies in renal allograft vascular rejection

Acute rejection with vascular involvement remains a challenging problem in renal allotransplantation. Fibrinoid necrosis of the arteries with secondary thrombotic occlusions is C4d negative in 50% of cases and has the worst prognosis among all allograft vascular lesions. Nonhuman leukocyte antigen (HLA) non-complement-fixing antibodies reacting to artery-specific antigens have been speculated to be responsible for causing severe vascular injury. We recently reported the presence of agonistic antibodies against the angiotensin II type 1 receptor (AT₁R-AA) in 16 recipients of renal allografts who had severe vascular rejection and malignant hypertension but who did not have anti-HLA antibodies. AT₁R-AA stimulate AT₁R and induce mediators of inflammation and thrombosis. Removal of AT₁R-AA by plasmapheresis in combination with pharmacologic AT₁R blockade leads to improved renal function and graft survival in AT₁R-AA-positive patients. We have shown that the analysis of the subtle diagnostic and mechanistic differences may help to identify patients at particular risk and improve outcome of rejections with vascular pathology.     

肾脏局部血管紧张素受体表达与IgA肾病病理损伤的相关性

目的 观察应用ARB类药物对肾脏局部血管紧张素受体表达的影响,探讨血管紧张素受体表达与IgAN肾病(immunoglobulin A nephrology,IgAN)肾脏病理损伤的关系.方法 选取2013年1月至2014年12月在中日友好医院肾内科行肾穿刺活检,且病理诊断为IgAN的患者172例,采用Lee分级方法进行病理分级,应用免疫组化方法检测AT1、AT2和MAS受体在肾活检组织中的表达,观察应用ARB类药物对上述三种血管紧张素受体的影响,分析三种受体表达水平与Lee分级的相关性.结果 Lee分级Ⅲ级IgAN患者中,应用ARB大于30 d者肾脏血管的AT1受体表达较未应用者显著减少,肾小球的AT2受体表达量较未应用者显著增多.IgAN患者肾脏血管、肾小管间质上AT1受体的表达水平与Lee分级存在显著正相关.Ⅴ级IgAN患者肾小球上AT2受体的表达量较Ⅰ~Ⅳ级患者显著增多.结论 应用ARB类药物治疗可影响IgAN患者肾脏局部AT1、AT2受体表达,肾脏局部AT1、AT2受体表达与IgAN肾脏病理损伤程度存在一定相关性.     

Role of intrarenal angiotensin II in glucocorticoid-induced renal vasodilation

Background. Although glucocorticoids elicit systemic hypertension, they are also demonstrated to cause marked increases in renal blood flow. The mechanism of this alteration, however, remains undetermined. Methods. Dogs were treated with dexamethasone (DEX) for 7 days, and renal, as well as systemic hemodynamic, responses to DEX were assessed. In addition, the role of intrarenal angiotensin (ANG) II in mediating the glucocorticoid-induced renal vasodilation was examined in conscious unrestrained dogs. Results. Seven-day treatment with DEX caused prominent increases in mean arterial pressure (MAP; from 80 ± 2 to 98 ± 5 mmHg) and in renal plasma flow (RPF; from 142 ± 4 to 191 ± 7 ml/min), with decreases in renal vascular resistance [RVR; from 0.26 ± 0.01 to 0.22 ± 0.01 mmHg/(ml/min)] and in the filtration fraction (FF; from 0.24 ± 0.01 to 0.20 ± 0.01). DEX treatment did not alter plasma ANG II levels, but enhanced candesartan-induced reduction in MAP. In contrast, the candesartan-induced increase in RPF (19 ± 2% increase) was completely abolished by DEX. DEX treatment markedly reduced renal tissue ANG II content (from 1.09 ± 0.07 to 0.71 ± 0.04 pg/mg tissue), which paralleled the response of renal tissue angiotensin-converting enzyme (ACE) activity (−20 ± 4%). Finally, intravenous ANG II administration caused a greater reduction in RPF during the DEX treatment period (−17 ± 2% vs −11 ± 1% in the control period). Conclusions. Glucocorticoids cause hypertension, but they also cause a paradoxical decrease in RVR and increase in RPF. The renal responses to candesartan and exogenous ANG II during DEX treatment suggest that the attenuation of intrarenal ANG-mediated vascular tone plays an important role in the altered renal hemodynamics. The decreased ANG tone is likely caused by reduced ANG II formation, resulting in part from suppressed ACE activity, but not from decreased sensitivity to ANG II. Received: November 1, 2000 / Accepted: April 5, 2001     

血管紧张素Ⅱ通过抑制AKT/蛋白激酶B磷酸化诱导肾小管上皮细胞凋亡

目的观察血管紧张素Ⅱ(AngⅡ)在诱导肾小管上皮细胞凋亡的信号传导是否有磷脂酰肌醇3激酶(PI3K)-AKT信号系统的参与,及该系统在诱导细胞凋亡中的作用。方法大鼠肾小管上皮细胞株NRK-52E分别与终浓度为0(对照组)、10-9mol/L、10-8mol/L、10-7mol/L、10-5mol/LAngⅡ共培养24h。用流式细胞仪检测细胞凋亡指数,用免疫组化方法检测增殖细胞核抗原(PCNA)的表达。Western印迹检测PI3K及磷酸化AKT和总AKT蛋白表达,AKT的磷酸化水平用473位丝氨酸磷酸化AKT(AKT-ser473)水平与总AKT水平的比值表示。结果随着AngⅡ浓度的增加,10-6mol/LAngⅡ组与对照组相比,凋亡指数显著增加[(22.7±1.41)%比(3.0±0.75)%,P<0.01]。而10-9mol/LAngⅡ组与对照组相比,PCNA指数显著增强[(47.54±2.6)%比(22.63±2.5)%,P<0.01]。与对照组相比,PI3K-p85蛋白的表达随AngⅡ浓度增加表现为先激活后抑制。AKT的磷酸化具有明显的AngⅡ浓度依赖性,随AngⅡ浓度的增加而逐渐受到抑制,并与细胞凋亡指数呈显著负相关(r=-0.90,P<0.01)。结论AngⅡ可以诱导肾小管上皮细胞凋亡并抑制细胞的增殖,可能部分是通过抑制PI3K-AKT信号传导途径实现的。     

Role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the development of hypertensive organ damage

Recently, a novel endothelial oxidized low-density lipoprotein (LDL) receptor, lectin-like oxidized LDL receptor (LOX)-1, has been identified by the expression cloning of cultured bovine aortic endothelial cells (BAEC). The experimental evidence has suggested that LOX-1 may contribute to the development of vascular injury. For example, LOX-1 is upregulated in aorta from hypertensive, diabetic, and hyperlipidemic model animals. Also, LOX-1 overexpression is observed in atherosclerotic regions and damaged kidneys. In hypertensive animals, not only antihypertensive drugs but also antioxidant agents suppress the LOX-1 overexpression. Peroxisome proliferator-activated receptor- (PPAR) activators inhibit cytokine-stimulated LOX-1 expression, possibly through their antioxidant effects, while, in contrast, LOX-1 generates reactive oxygen species (ROS). Therefore, ROS may play an important role in both the expression and function of LOX-1.     

血管紧张素Ⅱ灌注诱导大鼠肾脏血管紧张素转换酶2表达改变

目的 研究血管紧张素Ⅱ(AngⅡ)灌注后大鼠肾脏血管紧张素转换酶2(ACE2)表达的改变及其意义。 方法 雄性SD大鼠随机分为AngⅡ灌注组(400 ng&#8226;kg-1&#8226;min-1)、生理盐水灌注组和健康对照组，每组6只。测定28 天内大鼠血压及尿蛋白量变化。于第28天处死动物取肾，观察组织学改变，并用免疫组化、RT-PCR及Western印迹法检测ACE2表达及分布变化；凝胶电泳迁移率分析法(EMSA)检测核因子(NF)-κB的DNA结合活性变化。 结果 (1) AngⅡ灌注组大鼠血压升高，并出现明显蛋白尿。AngⅡ灌注后第28天，部分肾小球出现轻中度系膜增生，少数有节段性硬化；部分肾小管上皮细胞变性、坏死或萎缩，间质灶性炎性细胞浸润。(2) 健康大鼠肾脏ACE2主要分布于肾小管，以近端肾小管刷状缘分布最多。AngⅡ灌注后第28天，肾皮质ACE2 mRNA及蛋白表达均明显下降(P均< 0.05)，NF-κB结合活性显著增加(P < 0.05)。相关分析表明，ACE2表达与NF-κB结合活性之间呈负相关(r = -0.64，P < 0.01)。 结论 AngⅡ灌注可致大鼠肾脏ACE2表达明显下降，后者与肾损害的程度密切相关。肾脏ACE2表达下降可能是AngⅡ引起肾损害的重要机制     

血管紧张素Ⅱ通过ROS-EGFR-JNK-AP-1信号通路诱导肾小球系膜细胞增殖

目的 探讨血管紧张素Ⅱ（AngⅡ）是否通过活性氧-表皮生长因子受体-c-Jun氨基末端激酶-活化蛋白1（ROS-EGFR-JNK-AP-1）信号通路诱导肾小球系膜细胞增殖。 方法 体外培养人肾小球系膜细胞，用AngⅡ（100 nmol/L）、葡萄糖氧化酶（GO）（1 U/L）、血管紧张素受体拮抗剂洛沙坦（10 μmol/L）、乙酰半胱氨酸（NAC，10 μmol/L）、NADPH氧化酶抑制剂apocynin（10 μmol/L）、硫酸二亚苯基碘（DPI，10 μmol/L）、EGFR阻断剂AG1478（10 μmol/L）处理细胞。以未处理细胞为阴性对照。应用3H-胸腺嘧啶（3H-TdR）掺入法和细胞计数测定系膜细胞增殖；荧光探针2,7-二氯二氢荧光素乙酰乙酸（DCFDA）检测细胞内ROS 的产生；Western 印迹检测EGFR 和JNK 活化。 结果 AngⅡ（100 nmol/L） 可显著促进肾小球系膜细胞ROS 产生，AngⅡ 刺激60 min，系膜细胞产生ROS是对照组2.26 倍。AngⅡ可呈时间和剂量依赖性诱导系膜细胞EGFR 磷酸化，AngⅡ刺激5 min，EGFR 活化明显增加，至30 min 达到高峰，随AngⅡ刺激剂量增加，EGFR活化亦显著增强，AngⅡ（100 nmol/L） 刺激30 min，EGFR 磷酸化是对照组的3.96 倍。洛沙坦、NAC以及apocynin和 DPI 显著抑制AngⅡ诱导的EGFR 磷酸化，同时AG1478 几乎完全阻断AngⅡ诱导的系膜细胞增殖；洛沙坦、NAC、apocynin、DPI 和AG1478 显著抑制AngⅡ诱导的JNK 活化。 结论 ROS-EGFR-JNK-AP-1信号通路参与AngⅡ诱导的肾小球系膜细胞增殖。NADPH 氧化酶抑制剂和EGFR 受体拮抗剂能显著抑制AngⅡ诱导的系膜细胞增殖，可能是一种新的治疗途径。     

Hemodynamic, sympathetic and angiotensin II responses to PEEP ventilation before and during administration of isoflurane

Background: Positive end-expiratory pressure (PEEP) ventilation and isoflurane anesthesia may opposingly affect the sympathetic nervous and renin-angiotensin systems. This study was performed to elucidate the modulatory effects of isoflurane anesthesia on the neurohumoral and cardiovascular responses to PEEP.
Methods: Renin-angiotensin and sympathetic nervous activity were investigated in mechanically ventilated, normovolemic, chloralose anesthetized pigs before and during administration of 1.4% isoflurane. Arterial angiotensin II (All) concentrations were measured and systemic, mesenteric, hepatic and renal spillover of norepinephrine (NE-SO) were calculated using isotope dilution. Regional hemodynamic variables were investigated in parallel.
Results: PEEP10 alone moderately elevated All levels (+12.5 ± 4.9 pg/ml, P < 0.05) and increased systemic (+22±2.9 pmolmin100g^-1, P < 0.05) and notably mesenteric (+32±9.6 pmolmin100g^-1, P < 0.05) NE-SO. Blood flow decreased in all vascular beds studied. Except for in the liver, isoflurane generally reduced NE-SO compared to baseline but did not change All concentrations. Strikingly, the sympathoexcitatory response to PEEP10 was inhibited, whereas All increased markedly (+284±64 pg/ml, P < 0.05) during PEEP10 and isoflurane. Renal blood flow was significantly more reduced during PEEP10 and isoflurane compared to PEEP10 alone, whereas the magnitude of reductions were similar in the other vascular beds.
Conclusion: The data suggest that renin-angiotensin activation is important to attenuate the impact of PEEP ventilation on cardioavascular performance during administration of the sympathodepressant isoflurane. Interference with the renin-angiotensin system may cause cardiovascular decompensation in isoflurane anesthetized patients subjected to PEEP-ventilation.