Hippo 信号通路与炎症的研究进展

Hippo信号通路是由一系列发生级联反应激酶构成的,调控细胞增殖和凋亡的一条关键信号转导通路,该信号通路最先于果蝇体内发现,且进化上高度保守。在哺乳动物中,早期研究主要集中于Hippo信号在肿瘤、心血管系统、免疫系统等疾病的调控,随着对Hippo信号通路的研究不断深入,近年来研究发现,Hippo与某些炎症疾病相关,特别是以Hippo通路为信号传导的中心,与某些炎症因子的信号通路存在交互作用,进而参与炎症的发生、发展过程。本文就Hippo信号通路与免疫细胞分化发育、Toll样受体信号传导通路、TGF-β/Smad信号通路,以及与G蛋白偶联受体之间的相互作用来阐述Hippo信号通路对炎症的调控机制,为研究Hippo信号通路调控炎症的机理提供思路。     

T 细胞在急性肾损伤中的作用

急性肾损伤(AKI)是指各种原因引起的短时间内肾功能快速丢失的临床综合征,发生AKI 的患者进展为慢性肾脏病(CKD)的风险高,死亡率增加,给患者家庭和社会造成极大的经济负担。许多因素介导AKI 的发生发展,目前认为,固有免疫和适应性免疫介导的炎症反应参与了AKI 的起始、进展以及修复的各个阶段,而T 淋巴细胞在其中扮演了关键角色。本文将对T 细胞在AKI 中的作用的研究进展进行综述。     

细胞周期停滞:AKI向CKD转变的关键点

急性肾损伤(Acute Kidney Injury,AKI)向慢性肾脏病(Chronic Kidney Disease,CKD)的进展过程严重影响肾脏预后及患者生存质量,是目前研究热点之一,其中细胞周期停滞是AKI向CKD进展中一个重要的致病机制。其可能通过持续增加细胞因子及炎症因子生成和释放、上皮间充质转分化、细胞器应激/串扰、衰老激活、管周微血管稀疏等一系列适应性不良修复过程,加速AKI向CKD转变。故调控细胞周期有望成为预防、减缓甚至阻断AKI-CKD进展的新的靶点机制。     

Pin1通过抑制Wnt/β-catenin信号参与CKD-MBD的发病

慢性肾脏病-矿物质和骨异常（CKD-MBD）是慢性肾脏病（CKD）常见并发症之一。近年研究表明骨代谢异常在CKD早期即已出现,是CKD-MBD发生发展的中心环节。而骨细胞特异性Wnt/β-catenin信号的异常是造成CKD骨代谢紊乱的重要机制。肽酰脯氨酰胺同分异构酶（Pin1）依赖的磷酸化丝/苏-脯氨基酸基序异构是调控Wnt/β-catenin信号通路的重要途径,Pin1的调节异常能够改变Wnt/β-catenin信号的作用,可能参与CKD MBD的进展。本文旨在探讨Pin1通过抑制Wnt/β-catenin信号参与CKD-MBD的发病。     

Hippo通路在颅面器官发育中的作用

目的介绍Hippo通路在颅面部器官发育相关领域中的最新进展。方法广泛查阅近年来国内外关于Hippo通路各组分在调节颅面器官发育中的作用的相关研究,对相关功能及机制进行总结。结果 Hippo信号通路是由一系列进化保守的蛋白构成激酶级联反应,通过对细胞的增殖,凋亡及分化等多种事件的调节来参与颅面部器官发育。结论脊椎动物颅面部器官的发育需要一系列复杂有序的信号分子共同协调参与。Hippo通路在颅面发育中具有重要作用,有望为探索颅面畸形新的治疗靶点提供帮助。     

脂多糖诱导的急性肾损伤小鼠模型肾脏中JNK信号通路的激活

目的 探讨JNK信号通路激活在脂多糖(LPS)诱导的急性肾损伤(AKI)发病中的作用.方法 48只小鼠随机分为对照组和AKI组,分别检测血清尿素氮、肌酐以及胱抑素C,HE染色观察肾组织病理改变,免疫组化、West-ern blot检测肾组织p-JNK和p-c-Jun蛋白表达部位及强度,ELISA检测血中肿瘤坏死因子-α(TNF-α)及白介素1β(IL-1β)水平.结果 小鼠腹腔注射LPS后,血清尿素氮、肌酐、胱抑素C均较对照组均明显升高,肾组织病理损伤呈进行性加重.正常小鼠各时间点可见p-JNK和p-c-Jun在肾小管、肾小球系膜区有微量表达.AKI组小鼠p-JNK及p-c-Jun在肾小管等部位大量表达.与对照组相比,AKI组p-JNK和p-c-Jun蛋白水平在1h后即开始升高,以造模4h时增高最明显,30 h时逐渐下降.与之相应,血中TNF-α和IL-1β水平亦明显升高,于4h达峰值后逐渐下降.结论 JNK信号通路激活在LPS诱导的AKI发病中起重要作用,JNK信号通路活化后可诱发TNF-α和IL-1 β等炎性因子的表达,继而介导AKI的发生和发展.     

Hippo信号通路与肿瘤发生的研究进展

Hippo信号通路是近年来研究发现的能够协调细胞增殖、细胞死亡和细胞分化,调控组织生长的一个高度保守的生长控制信号通路,其核心成分是Yap/Taz等转录调控因子。该信号通路的组成原件包括Mst1/2、Sal、Last1/2和Mob1,这些蛋白具有肿瘤抑制功能,Yap/Taz具有致瘤作用。因此该信号通路与控制器官大小,癌症的发生有着密切的关系。本文主要介绍Hippo信号通路在器官大小控制和癌症发生中的作用。     

线粒体功能障碍在急性肾损伤向慢性肾脏疾病转变中的作用

急性肾损伤(AKI)是一种发病率较高的临床综合征,会使远期慢性肾脏病(CKD)的发病率明显上升,其机制目前尚不完全明确,可能包括细胞周期停滞、小管上皮周围毛细血管变少、炎性细胞浸润等。线粒体功能障碍在其中的作用主要包括导致了过度氧化应激、促进炎性反应的发生及进展、直接诱导肾小管细胞凋亡等。     

Wnt/β-catenin信号途径与肾脏疾病

Wnt/β-catenin信号途径参与了肾脏发育及肾肿瘤、肾纤维化、多囊肾、急性肾衰竭、糖尿病肾病等肾脏病的发病。该途径控制输尿管芽的发育并调节间充质细胞的肾形态发生过程;其表达异常参与了多种肾肿瘤的发病;Wnt/β-catenin信号的异常激活诱导肾小管上皮细胞、肾小球系膜细胞等肾脏固有细胞增殖或凋亡,导致多种慢性肾脏病的发生与发展。因而,Wnt/β-catenin信号途径在肾脏发育与疾病中的作用日益受到重视。     

巨噬细胞在肾纤维化发病机制和治疗中的研究进展

肾纤维化是肾脏组织受损后瘢痕修复的过程, 是各种慢性肾脏病(chronic renal diseases, CKD)的最终结果。巨噬细胞参与炎症性肾脏疾病的发病过程并与CKD的纤维化进展密切相关。巨噬细胞表型和功能在整个病程中变化复杂, 多种信号通路参与其中并介导纤维化的进程。文章概述了巨噬细胞表型和功能、在肾纤维化发病中的作用及靶向巨噬细胞对肾纤维化的治疗作用。     

Renal hypoxia in kidney disease: Cause or consequence?

Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a “common pathway” to both AKI and CKD still remains to be adequately tested.     

Notch in the kidney: development and disease

Notch signalling is a highly conserved cell-cell communication mechanism that regulates development, tissue homeostasis, and repair. Within the kidney, Notch has an important function in orchestrating kidney development. Recent studies indicate that Notch plays a key role in establishing proximal epithelial fate during nephron segmentation as well as the differentiation of principal cells in the renal collecting system. Notch signalling is markedly reduced in the adult kidney; however, increased Notch signalling has been noted in both acute and chronic kidney injury. Increased glomerular epithelial Notch signalling has been associated with albuminuria and glomerulosclerosis, while tubular epithelial Notch activation caused fibrosis development most likely inducing an improper epithelial repair pathway. Recent studies thereby indicate that Notch is a key regulator of kidney development, repair, and injury.     

单核巨噬细胞介导急性肾损伤发病的研究进展

急性肾损伤 (Acute Kidney Injury,AKI) 和慢性肾脏病 (Chronic Kidney Disease,CKD) 是最常见的肾损伤形式,已成为新的“公共健康问题”。高效识别肾脏高危易损者是目前临床精准监测、精准防治的迫切需要。肾损伤后的信号分子,特别是肾小管上皮细胞损伤后表达的小分子蛋白,能释放至尿液中,尿中水平与肾损伤程度密切相关,是新的肾损伤指标。本文围绕主要的尿液肾损伤生物标志物,介绍它们从基础发现到临床验证,再到临床应用的全过程,最后初步探讨尿液肾损伤标志物研究的未来方向。     

肾损伤标志物表达、作用及不同情况下的变化

背景：随着新型肾损伤标志物的不断发现及其在不同肾脏疾病中的表达及作用机制的阐明,肾损伤防治取得了重要进展。 目的：综述肾损伤标志物的研究进展。 方法：应用计算机检索2006年1月2011年10月PubMed数据库相关文章,检索词为“renal injury,markers”,并限定文章语言种类为English。同时计算机检索2006年1月2011年10月中国期刊全文数据库相关文章,检索词为“肾损伤,标志物”,并限定文章语言种类为中文。此外手工检索相关中英文会议文集。最终纳入符合标注的文献50篇。 结果与结论：肾损伤标志物在不同肾疾病中的预测及表达不同,按时间、结构、功能及标本来源可将其进行不同的划分。这些标志物不仅能早期监测肾脏疾病、评估急性肾损伤,且有助于判断慢性肾损伤的转归。近年来发现的肾损伤标志物其变化均较血肌酐早,且具有较高的灵敏性和特异性,但如何筛选并应用于临床,还需深入研究其在不同个体、不同时相及不同合并症或并发症影响下的变化情况,建立肾损伤的预警平台,以期达到早期诊断和治疗肾损伤的目的。     

Requirement of drug development for chronic renal disease: Other strategies than blockade of the renin-angiotensin system

The number of patients with chronic renal disease is increasing, hypertension and diabetes being major causes of it. Chronic renal disease progresses to the end-stage, of which a patient requires dialysis or transplantation, and thus prevention of progression of renal disease to the end-stage is a very important issue. Accumulating data indicate that angiotensin-converting enzyme (ACE) inhibitor is more effective than other antihypertensive drugs for treating chronic renal disease, since in addition to an antihypertensive effect, ACE inhibitor has a renoprotective effect. Although ACE inhibitor is more effective than other antihypertensive drugs, it only prevents the progression of chronic renal disease by less than 50%. Thus, in addition to blockers of the renin-angiotensin system, other types of drugs are required. Chronic renal disease progresses through a common pathway, regardless of the type of initial insult. This common pathway includes direct hemodynamic actions, modulation of glomerular cell injury, growth factor actions and induction of apoptosis. Blockade of this common pathway is one of the drug development strategies for chronic renal disease.     

The role of the immune system in kidney disease

The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play a central role in progression of chronic kidney disease. A dysregulated immune system can have either direct or indirect renal effects. Direct immune‐mediated kidney diseases are usually a consequence of autoantibodies directed against a constituent renal antigen, such as collagen IV in anti‐glomerular basement membrane disease. Indirect immune‐mediated renal disease often follows systemic autoimmunity with immune complex formation, but can also be due to uncontrolled activation of the complement pathways. Although the range of mechanisms of immune dysregulation leading to renal disease is broad, the pathways leading to injury are similar. Loss of immune homeostasis in renal disease results in perpetual immune cell recruitment and worsening damage to the kidney. Uncoordinated attempts at tissue repair, after immune‐mediated disease or non‐immune mediated injury, result in fibrosis of structures important for renal function, leading eventually to kidney failure. As renal disease often manifests clinically only when substantial damage has already occurred, new diagnostic methods and indeed treatments must be identified to inhibit further progression and promote appropriate tissue repair. Studying cases in which immune homeostasis is re‐established may reveal new treatment possibilities.