表观遗传学与肾脏疾病

表观遗传学(epigenetics)研究的是在DNA序列不发生改变的情况下,基因的表达和功能发生改变,并产生可遗传的表型.表观遗传学研究内容包括DNA甲基化、组蛋白修饰和非编码RNA.在肿瘤发生机制及治疗方面表观遗传学已作出很大的贡献,但在肾脏病领域表观遗传学应用的研究还很少. 一、表观遗传学 表观遗传学是传统遗传学的分支,由英国科学家Waddington提出[1],指在DNA序列不发生改变的情况下,基因的表达和功能发生改变,并产生可遗传的表型.表观遗传学大大丰富了传统遗传学的内容,使我们认识到基因组不仅包括DNA序列遗传信息,还包括表观遗传学信息.     

表观遗传学在骨性关节炎研究中的进展

骨性关节炎(osteoarthritis,OA)是一种最常见的以关节软骨退变为主要病理改变的年龄相关性退化疾病,可表现为不同程度的关节软骨丢失、骨质增生、软骨下骨改变和滑膜炎等.近年来越来越多的证据表明表观遗传修饰在OA发生发展中扮演着非常重要的作用.表观遗传学研究与DNA序列无关的基因表达调控,包括DNA甲基化、组蛋白修饰、miRNA、基因印记等.表观遗传调控可以作为研究OA发病机制的一个新思路.本文就表观遗传学与OA的相关性做一综述.     

DNA甲基化与肝癌

表观遗传学是指非遗传改变(DNA甲基化、组蛋白修饰以及miRNA等非编码RNA)对基因表达调控,这种调节不依赖基因序列的改变且可遗传,其中DNA甲基化是最常见的表观遗传现象。研究表明,在肝癌的发展过程中,表观遗传学改变起到了重要的作用,探讨DNA甲基化的致癌机制可为肿瘤诊治提供理论依据,同时也可作为生物标志物用于肿瘤早期诊断和预后评估。为此,将对肝癌中DNA甲基化改变的特征及其临床应用价值进行阐述。     

表观遗传学与皮肤肿瘤

表观遗传学（Epigenetics）主要研究DNA序列不发生变化时,基因表达异常的机制,以及这种改变又是如何在有丝分裂和减数分裂过程中遗传给后代。表观遗传学机制主要涉及DNA甲基化（DNA methylation）、组蛋白修饰（Histone modification）和microRNA调控（MicroRNA interference）[1]。     

DNA甲基化修饰与肾脏疾病

表观遗传学(epigenetics)是研究不涉及DNA序列改变的基因表达和调控的可遗传修饰,即探索从基因演绎为表型的过程和机制的一门新兴学科.DNA的甲基化是调节基因表达的一种表观遗传方式[1].DNA甲基化因其与人类发育和肿瘤的密切关系,已经成为表观遗传学的重要研究内容.所谓DNA甲基化是指在DNA甲基转移酶(DNMT)作用下,将s-腺苷甲硫氨酸(s-adenosylmethionine,SAM)的甲基基团共价结合到CpG二核苷酸的胞嘧啶5'碳位上的过程.     

临床肾脏学中表观遗传学的研究

表观遗传学(Epigenetios)是研究不涉及DNA序列变化,表型却发生可遗传改变的一门不同于遗传学的新学科,其研究内容包括DNA甲基化和组蛋白修饰等几个方面,任何一方面的异常都可能影响染色质的结构与基因表达.慢性肾脏疾病(Chronic kidney disease,CKD)是一种复杂性综合疾病,它受到遗传因素和表观遗传修饰的双重影响.尿毒症患者炎症、血脂异常、高同型半胱氨酸血症、氧化应激水平都可能导致整体DNA甲基化异常.目前,对于CKD的研究尚处于初期,本文就CKD相关的表观遗传学研究作一综述.     

间充质干细胞成软骨分化的表观遗传学研究

表观遗传学机制包括DNA甲基化,组蛋白修饰和microRNA,表观遗传学调控基因表达改变持久、可遗传并且不涉及DNA序列改变,各个领域中对于表观遗传学机制的研究和应用已经成为新的热点。软骨组织再生医学领域中的表观遗传学机制研究,为干细胞向软骨细胞分化以及软骨细胞终末分化提供了多种调控方式。但是,目前的研究主要是在体外常氧条件下,软骨组织工程细胞最终将应用于体内低氧环境中,低氧环境与表观遗传学机制之间相互影响将是研究者们需要关注的重点。本综述意在收集近年来干细胞成软骨分化中表观遗传学调控的研究成果以及各个研究领域中低氧环境与表观遗传学机制间的相互影响,希望能够为软骨组织工程细胞体内应用研究提供新的思路。     

临床肾脏学中表观遗传学的研究

表观遗传学(Epigenetios)是研究不涉及DNA序列变化,表型却发生可遗传改变的一门不同于遗传学的新学科,其研究内容包括DNA甲基化和组蛋白修饰等几个方面,任何一方面的异常都可能影响染色质的结构与基因表达.慢性肾脏疾病(Chronic kidney disease,CKD)是一种复杂性综合疾病,它受到遗传因素和表观遗传修饰的双重影响.尿毒症患者炎症、血脂异常、高同型半胱氨酸血症、氧化应激水平都可能导致整体DNA甲基化异常.目前,对于CKD的研究尚处于初期,本文就CKD相关的表观遗传学研究作一综述.     

表观遗传修饰与肝癌的关系

表观遗传学是指基因的核苷酸序列在不发生改变的情况下,基因表达了可遗传的表型变化.表观遗传机制的失调在人类恶性肿瘤包括肝癌发生、发展过程中发挥了重要作用.目前研究结果发现:大量表观遗传可调节有关基因靶点和信号转导通路,如DNA甲基化、组蛋白修饰、RNA调节基因沉默等与肝癌的发生和发展密切相关.探究这些异常的表观遗传机制对诊断和治疗肝癌有着重要的意义.     

绝经后骨质疏松症发病机制的表观遗传学研究进展

表观遗传学修饰是指在DNA序列未变化情况下发生可遗传的基因表达的变化,主要机制包括DNA甲基化、组蛋白修饰、非编码RNAs、染色质修饰等。绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)属于原发性骨质疏松症的一种,主要是由于绝经后女性激素水平改变等原因致使骨代谢失衡,骨微结构破坏,骨量减少。近年来,大量研究证实了表观遗传学参与绝经后骨质疏松症的发生发展,本文将从DNA甲基化、组蛋白修饰和非编码RNAs这三个方面综述绝经后骨质疏松症在表观遗传学方面的发病机制。     

Gene polymorphism association studies in dialysis: the nutrition-inflammation axis

Although traditional risk factors for cardiovascular disease are common in dialysis patients, they alone cannot explain the unacceptably high prevalence of vascular disease in this patient group. Much recent interest has therefore focused on the role of various nontraditional cardiovascular risk factors, such as inflammation, wasting, obesity, vascular calcification, and oxidative stress. In addition, genetic factors such as single nucleotide polymorphisms (SNPs) may significantly influence the immune response, the levels of inflammatory markers and body composition, as well as the prevalence of vascular calcification in this patient group. While genetic variations in the tumor necrosis factor (TNF)-alpha-308 and interleukin (IL)-10 -1082 SNPs seem to be consistently associated with adverse clinical outcome in end-stage renal disease (ESRD) patients, the results regarding genetic variations in the IL-6 gene have been conflicting. To elucidate the respective role of DNA polymorphisms in the IL-6 and C-reactive protein (CRP) genes, as well as genes that encode vascular calcification inhibitors (such as fetuin-A, matrix Gla protein, and osteoprotegerin), sufficiently powered studies are needed in which both the protein product and the specific phenotype are determined. In addition, polymorphisms in genes related to body composition may be excellent candidates for analysis in the ESRD population, since nutritional parameters are strongly associated with adverse events in these patients. It seems conceivable that in the future, prognostic or predictive multigene DNA assays (which allow a simultaneous and rapid assessment of multiple genetic variants) will provide nephrologists with a more precise approach for the identification of "high-risk" ESRD patients and the development of accurate individualized treatment strategies.     

Therapeutisches Potenzial der Stickstoffmonoxid-Synthase-Isoformen in Restenose, Transplantat- und Bypassarteriosklerose

The diverse biological effects of nitric oxide (NO) have led to intense research into its roles in vascular physiology and pathophysiology. Using recombinant DNA and gene transfer the effects of endogenous NO production by the family of NO synthase (NOS) enzymes can be elegantly studied in a variety of tissues. In addition, the feasibility of vascular NOS gene therapy has been demonstrated in animal models. However, technical and safety limitations have to be addressed before NOS gene therapy for cardiovascular disease is available for humans. Since NO exerts critical functions in vascular pathology, including atherosclerosis, post-angioplasty restenosis, vein graft atherosclerosis, transplant atherosclerosis and cardiac allograft vasculopathy, this article reviews recent progress in the field with a focus on potential future applications of NOS-modulating therapies.     

Bypass grafts: the state of the art

The treatment options for infra-renal arteriosclerotic occlusive (ASO) vascular disease have never been more varied. The history of open revascularization procedures now exceeds 60 years. This represents three generations of vascular surgeons, the most recent of whom have witnessed more than 30 years of endovascular surgery development and dissemination. Both open and endovascular treatments should be considered mature; moreover, we are improving our understanding of the strategies and tactics that lead to the clinical application of one approach instead of the other. There are other important factors in the choice of a treatment modality to be used for a specific patient. Prime among these is evolving patterns of occlusive disease and the increasing severity of arterial calcification.     

Novel aspects of endothelium-dependent regulation of vascular tone

The vascular endothelium plays a crucial role in the regulation of vascular homeostasis and in preventing the initiation and progress of cardiovascular disease by controlling mechanical functions of the underlying vascular smooth muscle. Three vasodilators: nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor, produced by the endothelium, underlie this activity. These substances act in a co-ordinated interactive manner to maintain normal endothelial function and operate as support mechanisms when one pathway malfunctions. In this review, we discuss recent advances in our understanding of how gender influences the interaction of these factors resulting in the vascular protective effects seen in pre-menopausal women. We also discuss how endothelial NO synthase (NOS) can act in both a pro- and anti-inflammatory action and therefore is likely to be pivotal in the initiation and time course of an inflammatory response, particularly with respect to inflammatory cardiovascular disorders. Finally, we review recent evidence demonstrating that it is not solely NOS-derived NO that mediates many of the beneficial effects of the endothelium, in particular, nitrite acts as a store of NO released during pathological episodes associated with NOS inactivity (ischemia/hypoxia). Each of these more recent findings has emphasized new pathways involved in endothelial biology, and following further research and understanding of the significance and mechanisms of these systems, it is likely that new and improved treatments for cardiovascular disease will result.     

Pathobiology of pulmonary hypertension: Impact on clinical management

Our previous studies showed how analysis of pulmonary vascular changes on lung biopsy tissue and on angiography added to the hemodynamic assessment of pulmonary vascular resistance in predicting the success of a surgical repair. Both the potential for heightened vasoreactivity in the early postoperative period and for reversibility of pulmonary vascular disease at later follow-up were correlated with qualitative and quantitative evaluation of arterial changes. The ability of continuous intravenous prostacylin to arrest progression and even induce regression of structurally advanced pulmonary vascular disease in some cases has led to rethinking how pathological material can be useful in clinical decision making. The presence of occlusive changes and particularly plexiform lesions was thought to represent irreversible disease, but the observation that ongoing cellular proliferation and connective tissue synthesis occurs even in advanced lesions thought to represent end stage ‘burnt-out’ lesions, led to re-evaluation of the potential of biologically reversing the disease process. Our laboratory has used clinical material, cultured cells, and studies in experimental animals to gain new insights into some of the mechanisms which lead to the progression of vascular changes, and has used this information in strategies aimed at arresting progression and, more recently, inducing regression of pulmonary hypertension and associated vascular lesions. Specifically, we have focused on the increased activity of an endogenous vascular elastase (EVE) and expression of the glycoproteins tenascin and fibronectin in the pathobiology of pulmonary hypertension. This report will first review our studies in children with congenital heart defects, assessment of reversibility of pulmonary hypertension, and then discuss more recent work addressing cellular and molecular mechanisms aimed at developing newer therapeutic strategies. Copyright © 2000 by W.B. Saunders Company     

Arteriosclerosis, calcium phosphate deposition and cardiovascular disease in uremia: current concepts at the bench

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. A growing body of data points to nontraditional risk factors, including disturbances in mineral metabolism, as important determinants of the extremely high cardiovascular morbidity and mortality rates in these patients. Disturbances in mineral metabolism, especially elevated calcium and phosphate levels, have been linked to vascular and valvular calcification, both of which are associated with poor prognosis in chronic kidney disease patients. This review highlights important recent findings regarding the etiology of vascular calcification, with special emphasis on pathways that may be particularly relevant in chronic kidney disease patients. RECENT FINDINGS: New studies indicate that not only vascular intimal calcification (associated with atherosclerosis) but also vascular medial calcification are correlated with decreased survival in chronic kidney disease patients. With the relatively recent recognition of vascular calcification as an actively regulated process, a growing list of inducers (calcium, phosphate, inflammatory cytokines) and inhibitors (matrix Gla protein, fetuin, pyrophosphate, osteopontin) have been discovered. Interesting recent evidence suggests that they may contribute to the prevalence of this pathology in chronic kidney disease patients. SUMMARY: Vascular calcification is associated with decreased survival in chronic kidney disease patients. Understanding the causes and regulatory factors controlling vascular calcification will help refine therapeutic modalities currently in use, as well as develop novel therapeutics to abate and potentially reverse this deleterious process.     

Hormone replacement therapy and peripheral vascular disease in women

Women have been shown to have a lower incidence of vascular disease when compared to men. However, the incidence of vascular disease increases as women progress through menopause and reaches an incidence similar to that of men later in life. Women with peripheral vascular disease often have a delay in diagnosis, a higher incidence of asymptomatic disease, and poorer outcome after interventions. The differences in outcome have been attributed to a number of factors such as anatomic and hormonal differences. It is thought that estrogen deficiency is at least partially responsible for the increased risk of developing vascular disease after menopause, and thus hormone replacement therapy has been considered as a method to prevent progression of vascular disease. Conclusions drawn from a number of recent studies have resulted in a divergent view of hormone replacement therapy (HRT). This article explores the risk of peripheral vascular disease in women and the current state of research on hormone replacement therapy. The aims of this review are to present current perspectives on gender differences in the pathogenesis and outcomes of peripheral arterial disease (PAD). The effect of estrogen on atherogenesis, the role it plays in modulating the vascular endothelium, and the current evidence of the effects of HRT on vascular pathology is discussed. The most recent HRT clinical trials and present evidence for the benefits and risks of postmenopausal hormone replacement therapy are summarized. The effect of these issues on treatment practices is explained and suggestions are made for future directions of HRT and PAD research.     

Oxidative stress and vascular damage in hypertension

Oxidative stress, a state of excessive reactive oxidative species activity, is associated with vascular disease states such as hypertension. In this review, we discuss the recent advances in the field of reactive oxidative species-mediated vascular damage in hypertension. These include the identification of redox-sensitive tyrosine kinases, the characterization of enzymatic sources of superoxide production in human blood vessels, and their relationship with vascular damage in atherosclerosis and hypertension. Finally, recent developments in the search for strategies to attenuate vascular oxidative stress are reviewed.     

When not to treat cutaneous vascular lesions with the pulsed dye laser

The availability of effective laser treatment for cutaneous vascular lesions has risen dramatically in recent years. At the same time, there has been a proliferation of laser providers with varying amounts of training-both medical and nonmedical. We report a series of four cases where patients presented for cosmetic evaluation of vascular lesions and were discovered to have more significant pathologic disease. In presenting these cases, we hope to illuminate a basic differential diagnosis that exists for cutaneous vascular lesions and remind healthcare providers that not all "cosmetic" concerns are benign in origin. There is a differential diagnosis that exists for cutaneous vascular lesions that is worth reviewing, and it should be considered in all patients presenting for laser treatment.     

Molecular and cellular mechanisms in vascular injury in hypertension: role of angiotensin II

PURPOSE OF REVIEW: Emerging evidence indicates that hypertension is a vascular disease associated with inflammation, induced through redox-sensitive mechanisms that are regulated by angiotensin II. This review focuses on the role of inflammation, oxidative stress and angiotensin II in vascular injury and discusses implications of these processes in hypertension. RECENT FINDINGS: The dogma that hypertension is primarily a consequence of hemodynamic alterations has changed over the recent past, with compelling evidence that high blood pressure is linked to vascular damage, oxidative stress and inflammation. Of the many factors implicated in hypertensive vascular disease, angiotensin II appears to be one of the most important. Angiotensin II, a multifunctional peptide regulating vascular contraction, growth and fibrosis, has recently been identified as proinflammatory mediator. Angiotensin II increases vascular permeability, promotes recruitment of inflammatory cells into tissues, and directly activates infiltrating immune cells, which further contribute to the inflammatory process. Moreover, angiotensin II participates in tissue repair and remodeling, by stimulating cell growth and fibrosis. Many of these processes are mediated through increased generation of reactive oxygen species (oxidative stress). SUMMARY: Inflammation, oxidative stress and hypertension are closely interrelated. Here we discuss the (patho)physiology of vascular inflammation in hypertension, focusing specifically on the role of angiotensin II and reactive oxygen species. By understanding molecular and cellular mechanisms of hypertensive vascular disease will allow for more targeted therapy and hopefully improved management and treatment of patients with hypertension.