Ⅰ醛固酮增多症大鼠血管重构发生机制的实验研究 Ⅱ后腹腔镜下根治性肾切除术及其应用解剖学研究
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摘要
研究背景：原发性醛固酮增多症是引起继发性高血压的常见原因之一，传统的观点认为该病在高血压人群的检出率约为1％～2％，甚至＜1％，但目前普遍认为其占高血压人群的比率在10％以上。原发性醛固酮增多症分为多种亚型，其中以产醛固酮的肾上腺腺瘤(APA)和特发性醛固酮增多症(IHA)最为常见。APA和单侧肾上腺增生患者首选治疗方法是一侧肾上腺切除术。腹腔镜下肾上腺切除术是一种理想的手术方式，目前已被公认是外科治疗肾上腺疾病的金标准。
尽管在临床实践中应用手术治疗原发性醛固酮症增多症已获得了良好疗效，但长期随访发现部分病人术后高血压改善不明显，仍需服用降压药物。文献报道APA切除后，其高血压控制率为33％～87％。原发性醛固酮症增多症，尤其是产醛固酮的肾上腺腺瘤，为何术后效果不理想?其原因目前尚不明确。多年来大量研究表明高血压可致血管重构：大血管(如主动脉)重构导致管壁僵硬度增加、顺应性减退；小血管重构致管腔狭窄引起外周阻力增加，这一现象在原发性醛固酮增多症患者同样存在。据此有学者认为外周小血管重构引起管腔狭窄，血管功能改变所致外周阻力增加参与了原发性醛固酮症增多症术后持续性高血压的发生。
血管重构是指在高血压过程中与之伴随的血管结构和功能的改变。主要表现为血管管壁增厚、壁腔比值增高以及随之产生的血管功能异常。血管壁的增厚，一种表现为内膜下间隙和中层细胞总体积和细胞外基质增加，中层肥厚并侵犯管腔，此种类型称为生长(肥厚性重构)；另一种是血管体积不变，但组成成分重新排布导致血管内外径缩小、管壁增厚，称为向心性重构，继发性高血压血管重构主要表现为前者。
国内外大量研究表明，醛固酮对心血管系统是一独立的致病因子，与原发性高血压相比，原发性醛固酮患者更易发生心血管重构。醛固酮通过参与炎症反应、纤维化、钙化以及细胞周期的调控，可不依赖于高血压而直接引起血管重构的发生。主要表现为血管平滑肌细胞(VSMCs)增生、肥大，细胞外基质成分如胶原、纤维粘连蛋白等合成增多，造成管壁增厚，尤其是中层增厚，管腔相对变窄，中层／管腔内径(M／L)比值增加，从而引起外周阻力增加。
醛固酮可刺激血管平滑肌细胞的增殖，在体外实验已获得证实，但具体分子机制尚不明确。鼠双微体-2基因(murine double minute2，MDM2)是一种核蛋白，最初在鼠双微体中发现，与p53形成复合体。已知MDM2参与调控p53的生物学作用，它可阻止p53介导的细胞凋亡或逆转p53引起的G1期停滞，促进细胞进入S期；此外，MDM2还被认为可逆转p53引起的G2期停滞，促进细胞由G2期停滞进入M期；另外，MDM2还可与RB蛋白发生作用，参与血管平滑肌细胞的生长；MDM2还可被Ras引发的Raf／MEK／MAP激酶通路调控，该通路不依赖p53作用，从而参与调节细胞的生长、凋亡过程，当MDM2过度表达时，可促进细胞的增殖。最近，Nakamura等报道在体外细胞实验中，醛固酮经其受体(MR)可促进人主动脉平滑肌细胞中MDM2的表达，认为PA术后持续高血压与MDM2的高表达，参与外周小动脉血管平滑肌细胞增殖，引起血管重构有关。
另外，研究表明醛固酮刺激血管重构这一过程中还有多种细胞因子的参与，如内皮素-1(ET-1)、表皮生长因子(EGF)、血小板源生长因子(PDGF)，转化生长因子(TGF-β)等。TGF-β家族是一多功能的多肽类细胞因子，参与调节细胞的生长、分化、迁移以及细胞外基质的代谢等过程。其中TGF-β1与心血管的关系尤为密切，离体和在体的实验都提示TGF-β1可促进血管平滑肌细胞增殖、迁移，影响各种细胞外基质(ECM)成分的代谢过程，如促进胶原蛋白、纤维连接蛋白、蛋白多糖的表达，同时抑制细胞外基质降解酶及纤溶酶原激活因子的合成，减少细胞外基质的降解，引起ECM合成和沉积增加，在血管重构中发生重要作用。
本研究首先在大鼠皮下埋置微量渗透泵，持续泵入醛固酮，建立醛固酮增多症大鼠模型，观察外周血管形态学的变化。进而我们应用RT-PCR、Western blotting、免疫组织化学以及天狼星红染色等方法分别检测MDM2、p53、TGF-β1及Ⅰ／Ⅲ型胶原基因在大鼠血管平滑肌中的表达有无改变；螺内酯是一种盐皮质激素受体拮抗剂，大量研究表明可改善醛固酮对心血管系统的有害效应，因此在本研究中我们同时检测了螺内酯对上述基因的表达有无影响。通过本研究我们试图从分子水平阐明高醛固酮作用下血管重构的发生机制，初步探讨原发性醛固酮症增多症患者术后持续高血压的发生原因及防治措施。
第一部分醛固酮增多症大鼠模型的建立
目的介绍一种建立醛固酮增多症大鼠模型的方法。
方法将SD大鼠随机分为三组，每组8只，分别为模型组、拮抗组及正常对照组。利用微量渗透泵这一给药系统，将其埋植在大鼠背部皮下建立醛固酮增多症模型，其中模型组经微量渗透泵持续释放醛固酮(1μg／h，4w)；拮抗组除给予等量醛固酮外，每日行螺内酯灌胃(100mg/kg／d)；正常对照组仅泵空白溶剂。尾套法检测大鼠血压，并测定血钾、钠、醛固酮浓度及血浆肾素活性。
结果成功建立醛固酮增多症大鼠模型，模型组大鼠2周后血压明显升高，血钾下降，呈现低肾素、高醛固酮特征，与对照组和拮抗组相比差异具统计学意义(P＜0．01)。
结论借助微量渗透泵这一载体，可成功建立醛固酮增多症动物模型，方法简单，成模率高，为研究原发性醛固酮增多症提供了较好的平台。
第二部分醛固酮及其受体拮抗剂对大鼠血管平滑肌MDM2及p53基因表达的影响
目的观察醛固酮对大鼠血管平滑肌鼠双微体-2基因(murine double minute2，MDM2)和p53基因表达的影响。
方法利用第一部分介绍的方法建立醛固酮增多症大鼠模型，并将SD大鼠分为三组(每组8只)：正常对照组、醛固酮组及螺内酯拮抗组。分别采用RT-PCR、Westernblotting、免疫组织化学技术检测血管平滑肌MDM2及p53基因表达，应用压力肌动描记器对大鼠肠系膜第三级动脉分支进行形态学测量。
结果与对照组相比，醛固酮组肠系膜小动脉中层增厚，中层／内径比值升高(P＜0．01)；醛固酮组血管平滑肌MDM2及p53基因表达升高；同时醛固酮组MDM2／p53表达比值亦明显高于对照组(P＜0．01)。螺内酯可抑制醛固酮的上述作用(P＜0．01)。
结论醛固酮可促进血管平滑肌细胞中MDM2的表达，后者可能通过促进血管平滑肌细胞的增殖参与血管重构的发生；p53表达上调可能是血管平滑肌细胞对高醛固酮刺激产生的一种保护性反应。螺内酯可拮抗醛固酮的效应，改善外周血管重构。
第三部分醛固酮及其受体拮抗剂对大鼠血管平滑肌TGF-β1、Ⅰ型胶原及Ⅲ型胶原表达的影响
目的观察醛固酮及其受体拮抗剂对大鼠血管平滑肌TGF-β1、Ⅰ型胶原及Ⅲ型胶原表达的影响，初步探讨原发性醛固酮增多症发生血管重构的可能机制。
方法利用第一部分介绍的方法建立醛固酮增多症大鼠模型，并将SD大鼠分为三组：正常对照组、醛固酮组及螺内酯拮抗组，每组8只。光镜下观察大鼠主动脉形态学变化并检测血管中层厚度及横截面积、血管内径；肠系膜小动脉形态学测量方法见第二部分。分别采用RT-PCR、Western blotting及免疫组织化学方法检测血管平滑肌TGF-β1的表达；应用RT-PCR检测Ⅰ型胶原及Ⅲ型胶原mRNA水平的表达；苦味酸-天狼星红染色偏振光下检测大鼠主动脉及肠系膜小动脉中Ⅰ型胶原及Ⅲ型胶原的含量。
结果(1)血管形态学测量：醛固酮组与其他两组相比，主动脉血管中层厚度及M/L比值无统计学差异；而肠系膜动脉血管中层厚度及M／L比值增加，管腔内径变小，差异具统计学意义(P＜0．01)；(2)醛固酮组主动脉平滑肌TGF-β1基因在mRNA及蛋白表达均明显高于其他两组(P＜0．01)；(3)与其他两组相比，醛固酮组主动脉平滑肌Ⅰ型及Ⅲ型胶原在转录水平表达均升高，而在翻译水平仅Ⅲ型胶原表达升高，血管中层总胶原和Ⅰ型胶原含量则无明显变化；(4)肠系膜动脉血管壁总胶原、Ⅰ型胶原及Ⅲ型胶原含量醛固酮组明显高于其他两组，差异具统计学意义(P＜0．01)；(4)螺内酯可下调醛固酮所致TGF-β1及Ⅰ型胶原的表达(P＜0．01)，但不能完全下调醛固酮对Ⅲ型胶原的表达，差异同样具有统计学意义(P＜0．05)。
结论醛固酮可能通过上调血管平滑肌TGF-β1的表达，进而促进Ⅰ型胶原及Ⅲ型胶原的表达，从而参与血管重构的发生；螺内酯可改善醛固酮的有害效应。
研究背景：根治性肾切除术最基本的原则是在肾筋膜外完整切除患肾。与开放手术相比，应用后腹腔镜技术进行根治性肾切除术目前尚无成熟的、规范化的手术操作方法。腹膜后间隙是腹后壁壁层腹膜与腹横筋膜之间解剖区域的总称，它上达横膈，下至盆部腹膜外间隙。自Gerota于1895年对肾筋膜描述以来，一些解剖学家和放射学家对腹膜后间隙内的筋膜结构和肾周间隙进行了大量研究。Meyers等通过放射解剖学研究，以肾筋膜为主要解剖标志，首先提出了肾旁前、肾周、肾旁后间隙的解剖学划分：肾旁前间隙位于壁腹膜与肾筋膜前层及侧锥筋膜之间；肾周间隙由肾前、后筋膜包绕所形成；肾旁后间隙位于肾后筋膜和侧锥筋膜后外方与腹横筋膜之间。此后至今，这一解剖学划分被广泛采用。正确认识以上筋膜及各间隙之间的关系，是顺利实施根治性肾切除术的关键。
目的：介绍后腹腔镜肾癌根治术，并对镜下肾周区域相关解剖结构进行研究。
方法：自2006年3月至2008年12月，共进行后腹腔镜肾癌根治术100例。根据肾筋膜外切除的原则，在“两个间隙、上下两极间”分离切除患肾：腹侧-肾旁前间隙(后腹膜与肾前筋膜之间)，背侧-肾旁后间隙(肾后筋膜与腰肌筋膜之间)；上极达膈下，下方到髂窝。术中辨认重要的解剖结构：后腹膜及其返折、肾前筋膜、侧锥筋膜、肾后筋膜、腰大肌及重要血管。
结果：除2例中转开放手术外，其余均获得成功。术中最常见的并发症是腹膜破裂，本组11例；无重要脏器及大血管损伤。手术时间50～185min，中位数时间为65min；术中估计失血量为25～600 mL，中位数失血量为60 mL。所有肿瘤手术切缘均为阴性。术后平均随访13(1～31)个月，全部无瘤生存，无一例局部复发或发生穿刺通道种植转移。
结论：后腹腔镜根治性肾切除术时，熟悉肾周重要的镜下解剖学结构，进入正确的分离层面，有利于提高手术安全性，减少副损伤。
Background:Primary aldosteronism (PA)is a secondary,endocrine-mediated form ofhypertension defined by an autonomous aldosterone overproduction.Recently publishedstudies from various geographic populations reported significantly higher prevalence of PAin hypertensive patients (ranging from 5% to 30%)than the previously published data(ranging from 1% to 2%).Since Conn's original report of the aldosterone-producingadenoma in 1954,many subtypes of primary aldosteronism have been described.The mostcommon subtypes are aldosterone-producing adenoma (APA)and bilateral idiopathichyperaldosteronism (IHA).
Because of the deleterious cardiovascular effects of aldosterone,normalization ofcirculating aldosterone level or aldosterone receptor blockade should be an important themanagement plan for all patients with PA.Unilateral laparoscopic adrenalectomy,whichcan result in normalization of hypokalemia in all patients with APA,is supposed to be anexcellent treatment option for patients with unilateral APA.However,the long-term curerate of hypertension after removal of the APA ranges widely in patients,from 33% to 87%.In IHA,the situation is worse as unilateral or bilateral adrenalectomy seldom corrects thehypertension.To date,the mechanisms of persistent hypertension are not completelyelucidated.Remodeling of resistance arteries is a hallmark of arterial hypertension and canbe implicated in the excess cardiovascular damage associated with hypertension.It was alsofound that vascular structural remodeling existed in PA patients' small resistance arteries,where the renin-angiotensin system is shut off.Thus,some scholars hold that vascularremodeling contributes to maintaining high BP values,even when the triggeringmechanisms have vanished in PA.
Vascular remodeling is defined as the vascular wall changes from dynamic and trophicstimuli resulting in vascular hypertrophy or rearrangement of vascular wall material.Several types of vascular remodeling have been recently described:Inward remodelingdescribes a decrease in lumen diameter,whereas outward remodeling refers to an increasein lumen diameter.Hypotrophic remodeling describes a decrease in the amount of vascularwall materialno matter whether the lumen diameter is decreased or increased,whereas eutrophic remodeling refers to an absence of change in the amount and properties of wallmaterial regardless of whether the lumen diameter is decreased or increased.In theseprocesses,hypertrophic inward vascular remodeling is the most one and is associated withan increase in wall thickness,an increase in wall-to-lumen ratio,and a decrease in lumendiameter.
Chronic sustained hypertension leads to structural changes oft he small and largearteries.These alterations consist of smooth muscle hypertrophy and hyperplasia,increaseddeposition of collagen,and“dilution”or destruction of elastin fibers.In addition,therecould be no growth of vascular wall materials but a“rearrangement”of them,which termed“remodeling.”These changes serve to increase wall thickness and the media-to-lumen ratioand to decrease the external and internal diameter of the vessel—all of which contribute toincreased systemic vascular resistance in the small arteries and increased impedance in thelarger arteries.
Recent accumulating lines of evidences from clinical and experimental studies havesuggested that direct cardiovascular effect of aldosterone contributes to the development ofcardiovascular injury via MRs in non-epithelial tissue.For instance,aldosterone has beenreported to induce expression of some genes involved in vascular fibrosis,calcification,andinflammation,all of which are considered important in pathology of vascular remodeling.Aldosterone also induce mitogenesis of vascular smooth muscle cells (VSMCs),resultingin vascular structural remodeling under the presence of angiotensinⅡ.However,aldosterone itself without the presence of angiotensinⅡis also considered to causecardiovascular injuries.Vascular structural remodeling in small resistance arteries has beenreported in patients with primary aldosteronism (PA),whose serum aldosterone levels wereelevated but serum angiotensinⅡlevel was markedly down-regulated.In addition,aldosterone itself has also been demonstrated to stimulate proliferation of VSMCs.Therefore,aldosterone may directly induce some MR-responsive gen.e associated inregulation of the cell cycle in VSMCs.
Nakamura and Suzuki recently reported that murine double minute oncogene 2(MDM2),which was originally cloned from a spontaneously transformed BALB/c 3T3 cellline,was possibly involved in VSMC proliferation through MR by aldosterone in vitro. MDM2 is a nuclear protein that forms a complex with p53 and inhibits p53-mediated geneexpression by concealing its transactivating domain.MDM2 is known to regulate thebiological activity of p53 by preventing p53-mediated apoptosis or reversing p53-inducedG1 block of the cell cycle,thus promoting the entry of cells into S phases throughformation of these complexes.P53 activates the transcription of MDM2 while MDM2conversely inhibits p53-mediated genes,and the two genes are involved in a feed-backregulatory loop.Besides,MDM2 has been considered to be involved in promoting the entryof cells from G2 into M phases by reversing p53-mediated G2 block of the cell cycle.Inaddition,MDM2 is known to interact both physically and functionally with the RB protein,which is also involved in VSMC growth.Finally,MDM2 was also reported to be regulatedby the Ras-driven Raf/MEK/MAP kinase pathway in a p53-independent manner.In theirstudy,Nakamura speculated that MDM2 may be possibly associated withaldosterone-induced vascular structural remodeling of human resistance arteries,whichmay result in persistent hypertension even after resection of aldosterone-producingadrenocortical adenoma.
Except hypertrophy or hyperplasia of VSMCs participated in the process of vascularremodeling,increased deposition of extracellular matrix is also important.Thisextracellular matrix is a complex mixture of structural proteins and glycoproteins,includingcollagens,fibronectins,and proteoglycans.These processes are mediated by severalmediators,such as endothelins 1 (ET-1),epidermal growth factor (EGF),platelet-derivedgrowth factor (PDGF)and transforming growth factor-β1 (TGF-β1),et al.TGF-β1 isone of these mediators and it plays an integral part in wound healing and fibrous-tissueformation.In addition,TGF-β1 is known to increase the synthesis of extracellular matrixproteins,inhibit their degradation (such as collagen typesⅠandⅢ)and promote thephenotypic conversion of fibroblasts into myofibroblasts.
In this study,we first used a drug delivery system which was implantedsubcutaneously on the back of rat,establishing of a rat model of hyperaldosteronism.Ratswere infused withaldosterone (1μg/h)subcutaneously via a mini-osmotic pump for 4weeks.Systolic BP was monitored by the tail-cuff method.The pathological changes ofaorta were observed and measured under microscope,and vascular changes of mesenteric arteries were evaluated using a pressurized myograph.Then we used reversetranscriptase-polymerase chain reaction (RT-PCR),Western blotting,immunohistochemistry and sirius red staining techniques to assess the expression level ofMDM2,p53,TGF-β1,collagen typesⅠandⅢin VSMCs,respectively.Spironolactone,amineralocorticoid receptor (MR)blocker,has been demonstrated to protect extrarenaltissues from various aldosterone-induced damage.In this study we also examined whetherspironolactone may also inhibit an induction of these aldosterone-induced genes product inVSMCs in vivo.Based on the study above,we aimed to elucidate the molecularmechanisms of vascular remodeling in hyperaldosteronism,and clarify the cause of thepersistent hypertension of APA and improve the prevention and cure measures.
PartⅠ
Establishment of a rat model of hyperaldosteronism
Objective:To introduce a method for establishing a rat model of hyperaldosteronism.
Methods:Using a drug delivery system (Osmotic Minipump)which was implantedsubcutaneously on the back of rat,Sprague-Dawley rats were randomly divided into threegroups (n=8 per group):model group,antagonistic group and normal control group.Theyreceived aldosterone (1μg/h),spironolactone (100 mg/kg/d,gastric gavage)plus the equaldoses of aldosterone,vehicle (60% propylene glycol + 10% ethanol + 30% ddH20,V/V)respectively.Systolic blood pressure was measured by the tail-cuff method weekly.Allanimals were sacrificed 4 weeks later,then serum Na~+、K~+、aldosterone and PRA weremeasured.
Results:The hyperaldosteronism models were successfully established.Two weeks later inaldosterone-infused group,the systolic blood pressure was markedly elevated,serum levelsof K+ and PRA were decreased,and plasma aldosterone level was increased compared withthose in the other two groups,there were statistical significance (P＜0.01),
Conclusion:Utilizing the osmotic minipump,the rat model of hyperaldosteronism can besuccessfully established.This model is a simple,effective method with high successful rate and low complication rate.It provides an efficient tool for studying the primaryaldosteronism.
PartⅡ
Effect of aldosterone and mineralocorticoid receptor antagoniston expression of MDM2 and p53 in rat aortic vascular smoothmuscle cells in vivo
Objective:To study the effect of aldosterone and mineralocorticoid receptor antagonist onexpression of murine double minute2 (MDM2)and p53 gene in rat aortic vascular smoothmuscle cells in vivo and address a potential role of the interaction of p53 with MDM2 forthe regulation of cellularity.
Methods:The rat models of hyperaldosteronism were established as previously describedin partⅠ.Sprague-Dawley rats (n=8 in each group)were randomly divided into three
groups:the normal control group,the aldosterone-infused group,and the antagonistic group.MDM2 and p53 gene expression in rat aortic smooth muscle cells were detected byRT-PCR,Western blotting and immunohistochemical staining.
Results:Aldosterone infusion increases MDM2 and p53 gene expression in rat aorta,however the ratio of MDM2/p53 was also increased compared with controls (P＜0.01).Allthe above detrimental effects of aldosterone could be inhibited by spironolactone (P＜0.01).
Conclusion:Aldosterone promotes the expression of MDM2 gene in aortic smooth musclecells in vivo,which can be inhibited by spironolactone.However,the increase of p53 geneexpression should be seen as a protective reaction to aldosterone resulting in oxidant stress.The fate of the cells maydepend not only on the presence of p53,but also on the relativeratios of MDM2 and p53 proteins.MDM2 is therefore considered one of themineralocorticoid-responsive genes that regulate cell proliferation of VSMCs,possiblyplaying an important role in aldosterone-induced vascular structural remodeling.
PartⅢ
Effect of aldosterone and mineralocorticoid receptor antagoniston expression of transforming growth factor-beta1,collagentypesⅠandⅢin rat vascular smooth muscle cells in vivo
Objective:To investigate the effect of aldosterone and spironolactone on the expressionof transforming growth factor-beta1(TGF-β1),collagen typesⅠandⅢin rat vascularsmooth muscle cells in vivo,which may help to elucidate the molecular mechanismresulting in vascular remodeling in primary aldosteronism.
Methods:The rat models of hyperaldosteronism were established as previously describedin partⅠ.Sprague-Dawley rats (n=8 in each group)were randomly assigned to three
groups:the normal control group,the aldosterone-infused group,and the antagonistic group.The pathological changes of aorta were observed and measured under microscope.Mesenteric small arteries were dissected and mounted on a micromyograph,and themedia-to-lumen ratio (M/L)was calculated.TGF-β1 expression in rat vascular smoothmuscle was detected by RT-PCR,Western blotting and immunohistochemical staining.Themessenger RNA level expression of collagen typesⅠandⅢin rat aortic vascular smoothmuscle were detected by RT-PCR.The total collagen and collagen subtypes content in ratvascular wall were detected using polarized light microscopy (Sirius red staining and imageanalysis).
Results:(1)With respect to the vascular structure of large aorta,there were no differencesamong three groups;Aldosterone infusion increased media width and media-to-lumen ratioof mesenteric resistance arteries compared with controls (P＜0.01).Spironolactonenormalized media and media-to-lumen ratio;(2)Both mRNA and protein levels ofTGF-β1 of aortic vascular smooth muscle were increased in aldosterone-infused rats(P＜0.01 vs controls);(3)Compared with the other two groups,both collagen typesⅠandⅢin mRNA level were increased in aldosterone-infused rats (P＜0.01);(4)With respect tothe protein level expression of collagen types in aortic media,only collagen typeⅢincreased in aldosterone-infused rats.However,the total collagenand typeⅠandⅢinmesenteric small arteries were significantly greater in aldosterone-infused rats than in the other two groups.(5)Spironolactone down-regulates the expression of TGF-β1 andcollagen typeⅠ(P＜0.01),and could not downregulate the expression of collagen typeⅢcompletely (P＜0.05).The differences were of statistical significance.
Conclusion:Aldosterone and its receptor antagonist can regulate the expression ofTGF-β1,and collagen typesⅠandⅢin vascular smooth muscle cells,which mayinfluence the process of vascular remodeling in primary aldosteronism.
Background:To carry out radical nephrectomy successfully,the most fundamentalprinciple is en-bloc dissection of the tumorous kidney outside the renal fascia.Astandardized procedure for retroperitoneoscopic radical nephrectomy (RRN)is lacking,soaccurate and thorough anatomical consideration of the renal area is crucial.Theretroperitoneum lies between the posterior parietal peritoneum anteriorly and thetransversalis fascia posteriorly.Since Gerota described the fascial layer around the kidneyin 1895,the structure of the retroperitoneal space has been studied for many years byanatomists and radiologists.Currently,the generally accepted viewpoints were proposed byMeyers and other scholars in a series of articles.According to their opinions,there at leastpresented three fasciae structures around the kidney:the anterior renal fascia (Gerotafascia),the posterior renal fascia (Zuckerkandl fascia),and the lateroconal fascia.Theretroperitoneum was divided into three distinct compartments by perirenal fasciae:(1)theanterior pararenal space between the parietal peritoneum and the anterior renal fascia.Superiorly it extends to the dome of the diaphragm,inferiorly it communicates with thepelvis;(2)the perirenal space between the anterior and posterior renal fasciae;(3)theposterior pararenal space between the posterior renal fascia and the transversalis fasciacontains only fat.It is open towards the pelvic cavity inferiorly but is limited medially byfusion of the posterior renal fascia with the fascia of the quadratus lumborum and psoasmuscles.Accurate anatomical recognization of the perirenal space and the fasciaeenveloping the kidney is the key to perform radical nephrectomy,no matter whether viaopen or laparoscopic approach.
Objective:To study the endoscopic anatomical structures in retroperitoneal space,and tointroduce our experiences in retroperitoneoscopic radical nephrectomy accordingly.
Methods:RRN was carried out at our institution in 100 patients from March 2006 toDecember 2008.Following the principle“outside the renal fascia”of radical nephrectomy,the entire surgical procedure was described as being along“two spaces”and“two poles”.The ventral aspect of the kidney was dissected in the anterior pararenal space between theparietal peritoneum and the anterior renal fascia.The dorsal aspect was dissected in the anterior psoas space between the posterior renal fascia and the lumbar muscles.Cephalicdissection was upward to the subdiaphragmatic area,whereas caudal dissection was downto the iliac fossa.Important anatomical structures such as the parietal peritoneum and itsreflexion,anterior renal fascia,lateroconal fascia,posterior renal fascia,and psoas muscleswere identified during the procedure.
Results:All procedures were successful except two cases which necessitated conversion toopen surgery.The commonest intraoperative complication was peritoneal effractions (11cases).No major intraoperative complications occurred.Median operative time was 65minutes (range,55-185 minutes).Median estimated blood loss was 60 mL (range,25-600mL).Surgical margins for all 100 specimens were negative for tumor.Local recurrences orport-site metastasis were not observed during a mean follow-up period of 13 months (range,1-31 months).
Conclusion:Based on the accurate anatomical visualization of the perirenal area and thefascial structures,our RRN technique enabled us to enter the correct anatomical planesposteriorly and anteriorly,and carry out the RRN smoothly while simultaneously adheringto oncological principles.
尽管在临床实践中应用手术治疗原发性醛固酮症增多症已获得了良好疗效，但长期随访发现部分病人术后高血压改善不明显，仍需服用降压药物。文献报道APA切除后，其高血压控制率为33％～87％。原发性醛固酮症增多症，尤其是产醛固酮的肾上腺腺瘤，为何术后效果不理想?其原因目前尚不明确。多年来大量研究表明高血压可致血管重构：大血管(如主动脉)重构导致管壁僵硬度增加、顺应性减退；小血管重构致管腔狭窄引起外周阻力增加，这一现象在原发性醛固酮增多症患者同样存在。据此有学者认为外周小血管重构引起管腔狭窄，血管功能改变所致外周阻力增加参与了原发性醛固酮症增多症术后持续性高血压的发生。
血管重构是指在高血压过程中与之伴随的血管结构和功能的改变。主要表现为血管管壁增厚、壁腔比值增高以及随之产生的血管功能异常。血管壁的增厚，一种表现为内膜下间隙和中层细胞总体积和细胞外基质增加，中层肥厚并侵犯管腔，此种类型称为生长(肥厚性重构)；另一种是血管体积不变，但组成成分重新排布导致血管内外径缩小、管壁增厚，称为向心性重构，继发性高血压血管重构主要表现为前者。
国内外大量研究表明，醛固酮对心血管系统是一独立的致病因子，与原发性高血压相比，原发性醛固酮患者更易发生心血管重构。醛固酮通过参与炎症反应、纤维化、钙化以及细胞周期的调控，可不依赖于高血压而直接引起血管重构的发生。主要表现为血管平滑肌细胞(VSMCs)增生、肥大，细胞外基质成分如胶原、纤维粘连蛋白等合成增多，造成管壁增厚，尤其是中层增厚，管腔相对变窄，中层／管腔内径(M／L)比值增加，从而引起外周阻力增加。
醛固酮可刺激血管平滑肌细胞的增殖，在体外实验已获得证实，但具体分子机制尚不明确。鼠双微体-2基因(murine double minute2，MDM2)是一种核蛋白，最初在鼠双微体中发现，与p53形成复合体。已知MDM2参与调控p53的生物学作用，它可阻止p53介导的细胞凋亡或逆转p53引起的G1期停滞，促进细胞进入S期；此外，MDM2还被认为可逆转p53引起的G2期停滞，促进细胞由G2期停滞进入M期；另外，MDM2还可与RB蛋白发生作用，参与血管平滑肌细胞的生长；MDM2还可被Ras引发的Raf／MEK／MAP激酶通路调控，该通路不依赖p53作用，从而参与调节细胞的生长、凋亡过程，当MDM2过度表达时，可促进细胞的增殖。最近，Nakamura等报道在体外细胞实验中，醛固酮经其受体(MR)可促进人主动脉平滑肌细胞中MDM2的表达，认为PA术后持续高血压与MDM2的高表达，参与外周小动脉血管平滑肌细胞增殖，引起血管重构有关。
另外，研究表明醛固酮刺激血管重构这一过程中还有多种细胞因子的参与，如内皮素-1(ET-1)、表皮生长因子(EGF)、血小板源生长因子(PDGF)，转化生长因子(TGF-β)等。TGF-β家族是一多功能的多肽类细胞因子，参与调节细胞的生长、分化、迁移以及细胞外基质的代谢等过程。其中TGF-β1与心血管的关系尤为密切，离体和在体的实验都提示TGF-β1可促进血管平滑肌细胞增殖、迁移，影响各种细胞外基质(ECM)成分的代谢过程，如促进胶原蛋白、纤维连接蛋白、蛋白多糖的表达，同时抑制细胞外基质降解酶及纤溶酶原激活因子的合成，减少细胞外基质的降解，引起ECM合成和沉积增加，在血管重构中发生重要作用。
本研究首先在大鼠皮下埋置微量渗透泵，持续泵入醛固酮，建立醛固酮增多症大鼠模型，观察外周血管形态学的变化。进而我们应用RT-PCR、Western blotting、免疫组织化学以及天狼星红染色等方法分别检测MDM2、p53、TGF-β1及Ⅰ／Ⅲ型胶原基因在大鼠血管平滑肌中的表达有无改变；螺内酯是一种盐皮质激素受体拮抗剂，大量研究表明可改善醛固酮对心血管系统的有害效应，因此在本研究中我们同时检测了螺内酯对上述基因的表达有无影响。通过本研究我们试图从分子水平阐明高醛固酮作用下血管重构的发生机制，初步探讨原发性醛固酮症增多症患者术后持续高血压的发生原因及防治措施。
第一部分醛固酮增多症大鼠模型的建立
目的介绍一种建立醛固酮增多症大鼠模型的方法。
方法将SD大鼠随机分为三组，每组8只，分别为模型组、拮抗组及正常对照组。利用微量渗透泵这一给药系统，将其埋植在大鼠背部皮下建立醛固酮增多症模型，其中模型组经微量渗透泵持续释放醛固酮(1μg／h，4w)；拮抗组除给予等量醛固酮外，每日行螺内酯灌胃(100mg/kg／d)；正常对照组仅泵空白溶剂。尾套法检测大鼠血压，并测定血钾、钠、醛固酮浓度及血浆肾素活性。
结果成功建立醛固酮增多症大鼠模型，模型组大鼠2周后血压明显升高，血钾下降，呈现低肾素、高醛固酮特征，与对照组和拮抗组相比差异具统计学意义(P＜0．01)。
结论借助微量渗透泵这一载体，可成功建立醛固酮增多症动物模型，方法简单，成模率高，为研究原发性醛固酮增多症提供了较好的平台。
第二部分醛固酮及其受体拮抗剂对大鼠血管平滑肌MDM2及p53基因表达的影响
目的观察醛固酮对大鼠血管平滑肌鼠双微体-2基因(murine double minute2，MDM2)和p53基因表达的影响。
方法利用第一部分介绍的方法建立醛固酮增多症大鼠模型，并将SD大鼠分为三组(每组8只)：正常对照组、醛固酮组及螺内酯拮抗组。分别采用RT-PCR、Westernblotting、免疫组织化学技术检测血管平滑肌MDM2及p53基因表达，应用压力肌动描记器对大鼠肠系膜第三级动脉分支进行形态学测量。
结果与对照组相比，醛固酮组肠系膜小动脉中层增厚，中层／内径比值升高(P＜0．01)；醛固酮组血管平滑肌MDM2及p53基因表达升高；同时醛固酮组MDM2／p53表达比值亦明显高于对照组(P＜0．01)。螺内酯可抑制醛固酮的上述作用(P＜0．01)。
结论醛固酮可促进血管平滑肌细胞中MDM2的表达，后者可能通过促进血管平滑肌细胞的增殖参与血管重构的发生；p53表达上调可能是血管平滑肌细胞对高醛固酮刺激产生的一种保护性反应。螺内酯可拮抗醛固酮的效应，改善外周血管重构。
第三部分醛固酮及其受体拮抗剂对大鼠血管平滑肌TGF-β1、Ⅰ型胶原及Ⅲ型胶原表达的影响
目的观察醛固酮及其受体拮抗剂对大鼠血管平滑肌TGF-β1、Ⅰ型胶原及Ⅲ型胶原表达的影响，初步探讨原发性醛固酮增多症发生血管重构的可能机制。
方法利用第一部分介绍的方法建立醛固酮增多症大鼠模型，并将SD大鼠分为三组：正常对照组、醛固酮组及螺内酯拮抗组，每组8只。光镜下观察大鼠主动脉形态学变化并检测血管中层厚度及横截面积、血管内径；肠系膜小动脉形态学测量方法见第二部分。分别采用RT-PCR、Western blotting及免疫组织化学方法检测血管平滑肌TGF-β1的表达；应用RT-PCR检测Ⅰ型胶原及Ⅲ型胶原mRNA水平的表达；苦味酸-天狼星红染色偏振光下检测大鼠主动脉及肠系膜小动脉中Ⅰ型胶原及Ⅲ型胶原的含量。
结果(1)血管形态学测量：醛固酮组与其他两组相比，主动脉血管中层厚度及M/L比值无统计学差异；而肠系膜动脉血管中层厚度及M／L比值增加，管腔内径变小，差异具统计学意义(P＜0．01)；(2)醛固酮组主动脉平滑肌TGF-β1基因在mRNA及蛋白表达均明显高于其他两组(P＜0．01)；(3)与其他两组相比，醛固酮组主动脉平滑肌Ⅰ型及Ⅲ型胶原在转录水平表达均升高，而在翻译水平仅Ⅲ型胶原表达升高，血管中层总胶原和Ⅰ型胶原含量则无明显变化；(4)肠系膜动脉血管壁总胶原、Ⅰ型胶原及Ⅲ型胶原含量醛固酮组明显高于其他两组，差异具统计学意义(P＜0．01)；(4)螺内酯可下调醛固酮所致TGF-β1及Ⅰ型胶原的表达(P＜0．01)，但不能完全下调醛固酮对Ⅲ型胶原的表达，差异同样具有统计学意义(P＜0．05)。
结论醛固酮可能通过上调血管平滑肌TGF-β1的表达，进而促进Ⅰ型胶原及Ⅲ型胶原的表达，从而参与血管重构的发生；螺内酯可改善醛固酮的有害效应。
研究背景：根治性肾切除术最基本的原则是在肾筋膜外完整切除患肾。与开放手术相比，应用后腹腔镜技术进行根治性肾切除术目前尚无成熟的、规范化的手术操作方法。腹膜后间隙是腹后壁壁层腹膜与腹横筋膜之间解剖区域的总称，它上达横膈，下至盆部腹膜外间隙。自Gerota于1895年对肾筋膜描述以来，一些解剖学家和放射学家对腹膜后间隙内的筋膜结构和肾周间隙进行了大量研究。Meyers等通过放射解剖学研究，以肾筋膜为主要解剖标志，首先提出了肾旁前、肾周、肾旁后间隙的解剖学划分：肾旁前间隙位于壁腹膜与肾筋膜前层及侧锥筋膜之间；肾周间隙由肾前、后筋膜包绕所形成；肾旁后间隙位于肾后筋膜和侧锥筋膜后外方与腹横筋膜之间。此后至今，这一解剖学划分被广泛采用。正确认识以上筋膜及各间隙之间的关系，是顺利实施根治性肾切除术的关键。
目的：介绍后腹腔镜肾癌根治术，并对镜下肾周区域相关解剖结构进行研究。
方法：自2006年3月至2008年12月，共进行后腹腔镜肾癌根治术100例。根据肾筋膜外切除的原则，在“两个间隙、上下两极间”分离切除患肾：腹侧-肾旁前间隙(后腹膜与肾前筋膜之间)，背侧-肾旁后间隙(肾后筋膜与腰肌筋膜之间)；上极达膈下，下方到髂窝。术中辨认重要的解剖结构：后腹膜及其返折、肾前筋膜、侧锥筋膜、肾后筋膜、腰大肌及重要血管。
结果：除2例中转开放手术外，其余均获得成功。术中最常见的并发症是腹膜破裂，本组11例；无重要脏器及大血管损伤。手术时间50～185min，中位数时间为65min；术中估计失血量为25～600 mL，中位数失血量为60 mL。所有肿瘤手术切缘均为阴性。术后平均随访13(1～31)个月，全部无瘤生存，无一例局部复发或发生穿刺通道种植转移。
结论：后腹腔镜根治性肾切除术时，熟悉肾周重要的镜下解剖学结构，进入正确的分离层面，有利于提高手术安全性，减少副损伤。
Background:Primary aldosteronism (PA)is a secondary,endocrine-mediated form ofhypertension defined by an autonomous aldosterone overproduction.Recently publishedstudies from various geographic populations reported significantly higher prevalence of PAin hypertensive patients (ranging from 5% to 30%)than the previously published data(ranging from 1% to 2%).Since Conn's original report of the aldosterone-producingadenoma in 1954,many subtypes of primary aldosteronism have been described.The mostcommon subtypes are aldosterone-producing adenoma (APA)and bilateral idiopathichyperaldosteronism (IHA).
Because of the deleterious cardiovascular effects of aldosterone,normalization ofcirculating aldosterone level or aldosterone receptor blockade should be an important themanagement plan for all patients with PA.Unilateral laparoscopic adrenalectomy,whichcan result in normalization of hypokalemia in all patients with APA,is supposed to be anexcellent treatment option for patients with unilateral APA.However,the long-term curerate of hypertension after removal of the APA ranges widely in patients,from 33% to 87%.In IHA,the situation is worse as unilateral or bilateral adrenalectomy seldom corrects thehypertension.To date,the mechanisms of persistent hypertension are not completelyelucidated.Remodeling of resistance arteries is a hallmark of arterial hypertension and canbe implicated in the excess cardiovascular damage associated with hypertension.It was alsofound that vascular structural remodeling existed in PA patients' small resistance arteries,where the renin-angiotensin system is shut off.Thus,some scholars hold that vascularremodeling contributes to maintaining high BP values,even when the triggeringmechanisms have vanished in PA.
Vascular remodeling is defined as the vascular wall changes from dynamic and trophicstimuli resulting in vascular hypertrophy or rearrangement of vascular wall material.Several types of vascular remodeling have been recently described:Inward remodelingdescribes a decrease in lumen diameter,whereas outward remodeling refers to an increasein lumen diameter.Hypotrophic remodeling describes a decrease in the amount of vascularwall materialno matter whether the lumen diameter is decreased or increased,whereas eutrophic remodeling refers to an absence of change in the amount and properties of wallmaterial regardless of whether the lumen diameter is decreased or increased.In theseprocesses,hypertrophic inward vascular remodeling is the most one and is associated withan increase in wall thickness,an increase in wall-to-lumen ratio,and a decrease in lumendiameter.
Chronic sustained hypertension leads to structural changes oft he small and largearteries.These alterations consist of smooth muscle hypertrophy and hyperplasia,increaseddeposition of collagen,and“dilution”or destruction of elastin fibers.In addition,therecould be no growth of vascular wall materials but a“rearrangement”of them,which termed“remodeling.”These changes serve to increase wall thickness and the media-to-lumen ratioand to decrease the external and internal diameter of the vessel—all of which contribute toincreased systemic vascular resistance in the small arteries and increased impedance in thelarger arteries.
Recent accumulating lines of evidences from clinical and experimental studies havesuggested that direct cardiovascular effect of aldosterone contributes to the development ofcardiovascular injury via MRs in non-epithelial tissue.For instance,aldosterone has beenreported to induce expression of some genes involved in vascular fibrosis,calcification,andinflammation,all of which are considered important in pathology of vascular remodeling.Aldosterone also induce mitogenesis of vascular smooth muscle cells (VSMCs),resultingin vascular structural remodeling under the presence of angiotensinⅡ.However,aldosterone itself without the presence of angiotensinⅡis also considered to causecardiovascular injuries.Vascular structural remodeling in small resistance arteries has beenreported in patients with primary aldosteronism (PA),whose serum aldosterone levels wereelevated but serum angiotensinⅡlevel was markedly down-regulated.In addition,aldosterone itself has also been demonstrated to stimulate proliferation of VSMCs.Therefore,aldosterone may directly induce some MR-responsive gen.e associated inregulation of the cell cycle in VSMCs.
Nakamura and Suzuki recently reported that murine double minute oncogene 2(MDM2),which was originally cloned from a spontaneously transformed BALB/c 3T3 cellline,was possibly involved in VSMC proliferation through MR by aldosterone in vitro. MDM2 is a nuclear protein that forms a complex with p53 and inhibits p53-mediated geneexpression by concealing its transactivating domain.MDM2 is known to regulate thebiological activity of p53 by preventing p53-mediated apoptosis or reversing p53-inducedG1 block of the cell cycle,thus promoting the entry of cells into S phases throughformation of these complexes.P53 activates the transcription of MDM2 while MDM2conversely inhibits p53-mediated genes,and the two genes are involved in a feed-backregulatory loop.Besides,MDM2 has been considered to be involved in promoting the entryof cells from G2 into M phases by reversing p53-mediated G2 block of the cell cycle.Inaddition,MDM2 is known to interact both physically and functionally with the RB protein,which is also involved in VSMC growth.Finally,MDM2 was also reported to be regulatedby the Ras-driven Raf/MEK/MAP kinase pathway in a p53-independent manner.In theirstudy,Nakamura speculated that MDM2 may be possibly associated withaldosterone-induced vascular structural remodeling of human resistance arteries,whichmay result in persistent hypertension even after resection of aldosterone-producingadrenocortical adenoma.
Except hypertrophy or hyperplasia of VSMCs participated in the process of vascularremodeling,increased deposition of extracellular matrix is also important.Thisextracellular matrix is a complex mixture of structural proteins and glycoproteins,includingcollagens,fibronectins,and proteoglycans.These processes are mediated by severalmediators,such as endothelins 1 (ET-1),epidermal growth factor (EGF),platelet-derivedgrowth factor (PDGF)and transforming growth factor-β1 (TGF-β1),et al.TGF-β1 isone of these mediators and it plays an integral part in wound healing and fibrous-tissueformation.In addition,TGF-β1 is known to increase the synthesis of extracellular matrixproteins,inhibit their degradation (such as collagen typesⅠandⅢ)and promote thephenotypic conversion of fibroblasts into myofibroblasts.
In this study,we first used a drug delivery system which was implantedsubcutaneously on the back of rat,establishing of a rat model of hyperaldosteronism.Ratswere infused withaldosterone (1μg/h)subcutaneously via a mini-osmotic pump for 4weeks.Systolic BP was monitored by the tail-cuff method.The pathological changes ofaorta were observed and measured under microscope,and vascular changes of mesenteric arteries were evaluated using a pressurized myograph.Then we used reversetranscriptase-polymerase chain reaction (RT-PCR),Western blotting,immunohistochemistry and sirius red staining techniques to assess the expression level ofMDM2,p53,TGF-β1,collagen typesⅠandⅢin VSMCs,respectively.Spironolactone,amineralocorticoid receptor (MR)blocker,has been demonstrated to protect extrarenaltissues from various aldosterone-induced damage.In this study we also examined whetherspironolactone may also inhibit an induction of these aldosterone-induced genes product inVSMCs in vivo.Based on the study above,we aimed to elucidate the molecularmechanisms of vascular remodeling in hyperaldosteronism,and clarify the cause of thepersistent hypertension of APA and improve the prevention and cure measures.
PartⅠ
Establishment of a rat model of hyperaldosteronism
Objective:To introduce a method for establishing a rat model of hyperaldosteronism.
Methods:Using a drug delivery system (Osmotic Minipump)which was implantedsubcutaneously on the back of rat,Sprague-Dawley rats were randomly divided into threegroups (n=8 per group):model group,antagonistic group and normal control group.Theyreceived aldosterone (1μg/h),spironolactone (100 mg/kg/d,gastric gavage)plus the equaldoses of aldosterone,vehicle (60% propylene glycol + 10% ethanol + 30% ddH20,V/V)respectively.Systolic blood pressure was measured by the tail-cuff method weekly.Allanimals were sacrificed 4 weeks later,then serum Na~+、K~+、aldosterone and PRA weremeasured.
Results:The hyperaldosteronism models were successfully established.Two weeks later inaldosterone-infused group,the systolic blood pressure was markedly elevated,serum levelsof K+ and PRA were decreased,and plasma aldosterone level was increased compared withthose in the other two groups,there were statistical significance (P＜0.01),
Conclusion:Utilizing the osmotic minipump,the rat model of hyperaldosteronism can besuccessfully established.This model is a simple,effective method with high successful rate and low complication rate.It provides an efficient tool for studying the primaryaldosteronism.
PartⅡ
Effect of aldosterone and mineralocorticoid receptor antagoniston expression of MDM2 and p53 in rat aortic vascular smoothmuscle cells in vivo
Objective:To study the effect of aldosterone and mineralocorticoid receptor antagonist onexpression of murine double minute2 (MDM2)and p53 gene in rat aortic vascular smoothmuscle cells in vivo and address a potential role of the interaction of p53 with MDM2 forthe regulation of cellularity.
Methods:The rat models of hyperaldosteronism were established as previously describedin partⅠ.Sprague-Dawley rats (n=8 in each group)were randomly divided into three
groups:the normal control group,the aldosterone-infused group,and the antagonistic group.MDM2 and p53 gene expression in rat aortic smooth muscle cells were detected byRT-PCR,Western blotting and immunohistochemical staining.
Results:Aldosterone infusion increases MDM2 and p53 gene expression in rat aorta,however the ratio of MDM2/p53 was also increased compared with controls (P＜0.01).Allthe above detrimental effects of aldosterone could be inhibited by spironolactone (P＜0.01).
Conclusion:Aldosterone promotes the expression of MDM2 gene in aortic smooth musclecells in vivo,which can be inhibited by spironolactone.However,the increase of p53 geneexpression should be seen as a protective reaction to aldosterone resulting in oxidant stress.The fate of the cells maydepend not only on the presence of p53,but also on the relativeratios of MDM2 and p53 proteins.MDM2 is therefore considered one of themineralocorticoid-responsive genes that regulate cell proliferation of VSMCs,possiblyplaying an important role in aldosterone-induced vascular structural remodeling.
PartⅢ
Effect of aldosterone and mineralocorticoid receptor antagoniston expression of transforming growth factor-beta1,collagentypesⅠandⅢin rat vascular smooth muscle cells in vivo
Objective:To investigate the effect of aldosterone and spironolactone on the expressionof transforming growth factor-beta1(TGF-β1),collagen typesⅠandⅢin rat vascularsmooth muscle cells in vivo,which may help to elucidate the molecular mechanismresulting in vascular remodeling in primary aldosteronism.
Methods:The rat models of hyperaldosteronism were established as previously describedin partⅠ.Sprague-Dawley rats (n=8 in each group)were randomly assigned to three
groups:the normal control group,the aldosterone-infused group,and the antagonistic group.The pathological changes of aorta were observed and measured under microscope.Mesenteric small arteries were dissected and mounted on a micromyograph,and themedia-to-lumen ratio (M/L)was calculated.TGF-β1 expression in rat vascular smoothmuscle was detected by RT-PCR,Western blotting and immunohistochemical staining.Themessenger RNA level expression of collagen typesⅠandⅢin rat aortic vascular smoothmuscle were detected by RT-PCR.The total collagen and collagen subtypes content in ratvascular wall were detected using polarized light microscopy (Sirius red staining and imageanalysis).
Results:(1)With respect to the vascular structure of large aorta,there were no differencesamong three groups;Aldosterone infusion increased media width and media-to-lumen ratioof mesenteric resistance arteries compared with controls (P＜0.01).Spironolactonenormalized media and media-to-lumen ratio;(2)Both mRNA and protein levels ofTGF-β1 of aortic vascular smooth muscle were increased in aldosterone-infused rats(P＜0.01 vs controls);(3)Compared with the other two groups,both collagen typesⅠandⅢin mRNA level were increased in aldosterone-infused rats (P＜0.01);(4)With respect tothe protein level expression of collagen types in aortic media,only collagen typeⅢincreased in aldosterone-infused rats.However,the total collagenand typeⅠandⅢinmesenteric small arteries were significantly greater in aldosterone-infused rats than in the other two groups.(5)Spironolactone down-regulates the expression of TGF-β1 andcollagen typeⅠ(P＜0.01),and could not downregulate the expression of collagen typeⅢcompletely (P＜0.05).The differences were of statistical significance.
Conclusion:Aldosterone and its receptor antagonist can regulate the expression ofTGF-β1,and collagen typesⅠandⅢin vascular smooth muscle cells,which mayinfluence the process of vascular remodeling in primary aldosteronism.
Background:To carry out radical nephrectomy successfully,the most fundamentalprinciple is en-bloc dissection of the tumorous kidney outside the renal fascia.Astandardized procedure for retroperitoneoscopic radical nephrectomy (RRN)is lacking,soaccurate and thorough anatomical consideration of the renal area is crucial.Theretroperitoneum lies between the posterior parietal peritoneum anteriorly and thetransversalis fascia posteriorly.Since Gerota described the fascial layer around the kidneyin 1895,the structure of the retroperitoneal space has been studied for many years byanatomists and radiologists.Currently,the generally accepted viewpoints were proposed byMeyers and other scholars in a series of articles.According to their opinions,there at leastpresented three fasciae structures around the kidney:the anterior renal fascia (Gerotafascia),the posterior renal fascia (Zuckerkandl fascia),and the lateroconal fascia.Theretroperitoneum was divided into three distinct compartments by perirenal fasciae:(1)theanterior pararenal space between the parietal peritoneum and the anterior renal fascia.Superiorly it extends to the dome of the diaphragm,inferiorly it communicates with thepelvis;(2)the perirenal space between the anterior and posterior renal fasciae;(3)theposterior pararenal space between the posterior renal fascia and the transversalis fasciacontains only fat.It is open towards the pelvic cavity inferiorly but is limited medially byfusion of the posterior renal fascia with the fascia of the quadratus lumborum and psoasmuscles.Accurate anatomical recognization of the perirenal space and the fasciaeenveloping the kidney is the key to perform radical nephrectomy,no matter whether viaopen or laparoscopic approach.
Objective:To study the endoscopic anatomical structures in retroperitoneal space,and tointroduce our experiences in retroperitoneoscopic radical nephrectomy accordingly.
Methods:RRN was carried out at our institution in 100 patients from March 2006 toDecember 2008.Following the principle“outside the renal fascia”of radical nephrectomy,the entire surgical procedure was described as being along“two spaces”and“two poles”.The ventral aspect of the kidney was dissected in the anterior pararenal space between theparietal peritoneum and the anterior renal fascia.The dorsal aspect was dissected in the anterior psoas space between the posterior renal fascia and the lumbar muscles.Cephalicdissection was upward to the subdiaphragmatic area,whereas caudal dissection was downto the iliac fossa.Important anatomical structures such as the parietal peritoneum and itsreflexion,anterior renal fascia,lateroconal fascia,posterior renal fascia,and psoas muscleswere identified during the procedure.
Results:All procedures were successful except two cases which necessitated conversion toopen surgery.The commonest intraoperative complication was peritoneal effractions (11cases).No major intraoperative complications occurred.Median operative time was 65minutes (range,55-185 minutes).Median estimated blood loss was 60 mL (range,25-600mL).Surgical margins for all 100 specimens were negative for tumor.Local recurrences orport-site metastasis were not observed during a mean follow-up period of 13 months (range,1-31 months).
Conclusion:Based on the accurate anatomical visualization of the perirenal area and thefascial structures,our RRN technique enabled us to enter the correct anatomical planesposteriorly and anteriorly,and carry out the RRN smoothly while simultaneously adheringto oncological principles.
引文
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