足细胞损伤与糖尿病肾病

糖尿病肾病逐步成为我国终末期肾病的主要病因。在糖尿病肾病的发病过程中,足细胞的损伤扮演着举足轻重的角色。近年来,随着对肾小球足细胞的研究深入,发现足细胞的表观遗传修饰、氧化应激、糖代谢异常、血流动力学改变、炎性细胞因子、胰岛素抵抗等损伤机制及相关蛋白的影响作用,对糖尿病肾病的调控机制及疾病进展具有重要意义。     

糖尿病肾病的表观遗传学机制

表观遗传学是指DNA序列不发生变化的情况下基因表达发生的可遗传的改变.大量的研究发现,表观遗传机制参与调控糖尿病肾病的肾脏纤维化、足细胞凋亡、慢性炎性反应、氧化应激等各个病理生理过程.     

O连接N-乙酰氨基葡萄糖糖基化修饰与糖尿病肾病的关系

O连接N-乙酰氨基葡萄糖(O-GlcNAc)糖基化修饰是一种常见的蛋白质翻译后修饰,其在胰岛素抵抗及糖尿病并发症中发挥着重要作用。近年来相关研究证明O-GlcNAc糖基化修饰与糖尿病肾病密切相关,高糖状态下进入氨基己糖生物合成途径的葡萄糖通量增加,O-GlcNAc糖基化修饰水平增加,其通过修饰特定的蛋白,诱导基底膜损伤、细胞肥大、足细胞功能障碍、间质纤维化等病理改变,参与糖尿病肾病的发生发展。抑制O-GlcNAc糖基化修饰可减轻相关组织的糖毒性,延缓向终末期肾病进展,为临床诊疗提供针对性策略。     

足细胞和糖尿病及其肾病

肾小球足细胞损伤和丢失是肾小球硬化形成和发展的关键因素。糖尿病时足细胞可出现密度和数量减少、足突增宽、足细胞脱落等改变,且可从尿中丢失,继而导致糖尿病肾病的发生。高血糖、高血压、氧化应激及一氧化氮等可直接损伤足细胞,并抑制α3β1整合素、nephrin的表达,促进血管内皮生长因子、Ⅳ型胶原、糖基化终末产物受体、转化生长因子β等的表达而加重足细胞损伤。因而,探索足细胞损伤在糖尿病肾病发生、发展中的病理发展过程对糖尿病肾病的防治具有重要意义。     

足细胞和糖尿病及其肾病

肾小球足细胞损伤和丢失是肾小球硬化形成和发展的关键因素。糖尿病时足细胞可出现密度和数量减少、足突增宽、足细胞脱落等改变，且可从尿中丢失，继而导致糖尿病肾病的发生。高血糖、高血压、氧化应激及一氧化氮等可直接损伤足细胞，并抑制α3β1整合素、nephrin的表达，促进血管内皮生长因子、Ⅳ型胶原、糖基化终末产物受体、转化生长因子β等的表达而加重足细胞损伤。因而，探索足细胞损伤在糖尿病肾病发生、发展中的病理发展过程对糖尿病肾病的防治具有重要意义。     

表观遗传调控在胰岛β细胞功能调控中的研究进展

表观遗传是指在DNA序列不发生改变情况下,基因表达发生可遗传性改变的现象.表观遗传在疾病发生发展中发挥重要作用,其机制十分复杂,包括DNA甲基化、组蛋白修饰和非编码RNA等.2型糖尿病是一种由遗传和环境因素共同作用而发生的复杂多基因遗传性疾病,其病因和发病机制目前尚未完全阐明.近年研究发现,表观遗传直接或间接调控胰岛β细胞的发育、分化、分泌功能以及机体对胰岛素的敏感性,参与2型糖尿病的发生和发展.对表观遗传调控的研究将为阐明2型糖尿病发病机制,及预防和治疗2型糖尿病提供新的思路和靶点.     

2型糖尿病中胰岛β细胞的表观遗传研究进展

目前,糖尿病在世界范围内迅速蔓延,且预计未来10年中将出现更加迅猛的进展,成为亟待解决的重大公共卫生问题。胰岛β细胞功能缺陷是T2DM的关键。表观遗传学不同于传统遗传学,它是在不改变DNA序列的基础上发生的可遗传改变,通过调节组蛋白修饰、DNA甲基化及微小RNA等表观标记的变化影响基因表达活性。近年来,表观遗传学成为解释胰岛β细胞损伤机制的有力工具。本文围绕以上3部分对胰岛β细胞表观遗传学变化的发生发展机制进行评述。深入认识胰岛β细胞损伤的原因对预防糖尿病的发生发展有重要意义。     

表观遗传学与糖尿病及其并发症

表观遗传学是指在不改变基因组核苷酸序列的前提下,基因的表达水平与功能发生改变,并产生可遗传的表型.年龄、肥胖、营养和体育锻炼等环境因素与遗传因素相互作用,导致DNA甲基化,组蛋白修饰,RNA干扰等表观遗传修饰,促使免疫紊乱、炎性反应和胰岛素抵抗的发生,产生“代谢记忆”,参与糖尿病并发症的发生、发展.表观遗传机制在调控糖尿病病程中起了重要作用,其可逆转的特性为临床治疗和预防糖尿病并发症提供了新的思路.     

足细胞与糖尿病肾病关系的若干研究进展

足细胞在维持肾小球滤过屏障完整性及限制血浆蛋白的滤出方面发挥重要作用,足细胞的损伤可部分解释肾小球滤过屏障结构及功能的改变的原因。在糖尿病肾病早期,足细胞损伤已出现,并可进一步导致。肾脏损伤。本文就足细胞与糖尿病肾病中若干研究进展作简要综述。     

微小RNA在糖尿病肾病发生发展中的作用

糖尿病肾病(DN)是糖尿病主要的微血管并发症,已经成为我国慢性肾脏疾病的主要病因之一。DN的发病机制是多因素的。深入了解DN的发病机制,寻找新的诊断及治疗靶点至关重要。微小RNA是普遍存在的非编码小分子RNA,起转录后调节作用,其通过多种信号途径介导了肾组织纤维化、炎症反应、足细胞凋亡等DN的病理生理改变,并在单核苷酸多态性、表观遗传修饰等方面参与了DN的发生发展。同时,循环微小RNA可在多种体液中的稳定存在也为其成为早期诊断靶点提供了依据。但是微小RNA在DN中的研究及临床应用仍有极大的挑战。     

Cell biology of diabetic nephropathy: Roles of endothelial cells,tubulointerstitial cells and podocytes

Diabetic nephropathy is the major cause of end‐stage renal failure throughout the world in both developed and developing countries. Diabetes affects all cell types of the kidney, including endothelial cells, tubulointerstitial cells, podocytes and mesangial cells. During the past decade, the importance of podocyte injury in the formation and progression of diabetic nephropathy has been established and emphasized. However, recent findings provide additional perspectives on pathogenesis of diabetic nephropathy. Glomerular endothelial damage is already present in the normoalbuminuric stage of the disease when podocyte injury starts. Genetic targeting of mice that cause endothelial injury leads to accelerated diabetic nephropathy. Tubulointerstitial damage, previously considered to be a secondary effect of glomerular protein leakage, was shown to have a primary significance in the progression of diabetic nephropathy. Emerging evidence suggests that the glomerular filtration barrier and tubulointerstitial compartment is a composite, dynamic entity where any injury of one cell type spreads to other cell types, and leads to the dysfunction of the whole apparatus. Accumulation of novel knowledge would provide a better understanding of the pathogenesis of diabetic nephropathy, and might lead to a development of a new therapeutic strategy for the disease.     

Epigenetics: mechanisms and implications for diabetic complications

Epigenetic modifications regulate critical functions that underlie chromosome metabolism. Understanding the molecular changes to chromatin structure and the functional relationship with altered signaling pathways is now considered to represent an important conceptual challenge to explain diabetes and the phenomenon of metabolic or hyperglycemic memory. Although it remains unknown as to the specific molecular mechanisms whereby hyperglycemic memory leads to the development of diabetic vascular complications, emerging evidence now indicates that critical gene-activating epigenetic changes may confer future cell memories. Chemical modification of the H3 histone tail of lysine 4 and 9 has recently been identified with gene expression conferred by hyperglycemia. The persistence of these key epigenetic determinants in models of glycemic variability and the development of diabetic complications has been associated with these primary findings. Transient hyperglycemia promotes gene-activating epigenetic changes and signaling events critical in the development and progression of vascular complications. As for the role of specific epigenomic changes, it is postulated that further understanding enzymes involved in writing and erasing chemical changes could transform our understanding of the pathways implicated in diabetic vascular injury providing new therapeutic strategies.     

Xanthine oxidoreductase inhibitor topiroxostat ameliorates podocyte injury by inhibiting the reduction of nephrin and podoplanin

BackgroundTopiroxostat, an inhibitor of xanthine oxidoreductase (XOR) was shown to reduce urinary albumin excretion of hyperuricemic patients with chronic kidney disease. However, its pharmacological mechanism is not well understood. In this study, we examined the effects of topiroxostat on glomerular podocytes. Podocyte is characterized by foot process and a unique cell-cell junction slit diaphragm functioning as a final barrier to prevent proteinuria.MethodsThe effects of topiroxostat on the expressions of podocyte functional molecules were analysed in db/db mice, a diabetic nephropathy model, anti-nephrin antibody-induced rat podocyte injury model and cultured podocytes treated with adriamycin.ResultsTopiroxostat treatment ameliorated albuminuria in db/db mice. The expression of desmin, a podocyte injury marker was increased, and nephrin and podocin, key molecules of slit diaphragm, and podoplanin, an essential molecule in maintaining foot process were downregulated in db/db mice. Topiroxostat treatment prevented the alterations in the expressions of these molecules in db/db mice. XOR activity in kidney was increased in rats with anti-nephrin antibody-induced podocyte injury. Topiroxostat treatment reduced XOR activity and restored the decreased expression of nephrin, podocin and podoplanin in the podocyte injury. Furthermore, topiroxostat enhanced the expression of podoplanin in injured human cultured podocytes.ConclusionsPodocyte injury was evident in db/db mice. Topiroxostat ameliorated albuminuria in diabetic nephropathy model by preventing podocyte injury. Increase of XOR activity in kidney contributes to development of podocyte injury caused by stimulation to slit diaphragm. Topiroxostat has an effect to stabilize slit diaphragm and foot processes by inhibiting the reduction of nephrin, podocin and podoplanin.     

艾塞那肽对糖尿病肾病小鼠足细胞的保护作用

目的探讨艾塞那肽对糖尿病肾病小鼠足细胞的作用。方法通过给予C57BL/6J小鼠高脂饮食并注射链脲佐菌素建立糖尿病肾病模型,按随机数字表法将其分为糖尿病肾病对照组(DN组,n=8)、艾塞那肽干预组(DN+Ex组,n=8)。同时将普通饲料喂养的C57BL/6J小鼠作为正常对照组(NC组,n=8)。干预结束后,测定血糖、肾功能和尿微量白蛋白/肌酐比值,采用过碘酸希夫染色(PAS)观察小鼠肾小球病理学改变,实时定量PCR分析肾小球组织中促纤维化分子Ⅳ型胶原蛋白(Collagen Ⅳ)、转化生长因子-β(TGF-β)和纤维连接蛋白(Fibronectin)基因转录水平,免疫荧光染色及电镜观察足细胞损伤及凋亡情况,Western印迹法检测肾小球组织中裂孔膜肾病蛋白(Nephrin)、活化型半胱氨酸天冬氨酸蛋白酶3(Cleaved caspase-3)、蛋白激酶B(Akt)和磷酸化Akt(p-Akt)表达水平。结果与DN组相比,DN+Ex组小鼠尿微量白蛋白/肌酐比值显著降低(P<0.01)。PAS染色及分析发现,艾塞那肽干预治疗改善了糖尿病肾病小鼠的肾小球系膜基质增生和肾小球肥大(P<0.05)。实时定量PCR显示,与DN组小鼠相比,DN+Ex组小鼠的肾小球组织中Collagen Ⅳ、TGF-β和Fibronectin基因表达下调(P<0.01)。免疫荧光染色和电镜显示,艾塞那肽干预治疗改善了糖尿病肾病小鼠的足细胞损伤及凋亡。Western印迹法发现,艾塞那肽干预后糖尿病小鼠肾小球组织中的Nephrin水平升高(P<0.01)、Cleaved caspase-3水平下降(P<0.01)、p-Akt水平升高(P<0.01)。结论艾塞那肽能够改善糖尿病肾病小鼠的足细胞损伤及凋亡,减少蛋白尿,从而延缓糖尿病肾病的进展。这种保护作用可能与激活肾小球中磷酸肌醇3-激酶(PI3K)/Akt信号通路有关。     

Podocytes as a target of insulin

Diabetic nephropathy (DN) presents with a gradual breakdown of the glomerular filtration barrier to protein, culminating in widespread glomerular damage and renal failure. The podocyte is the central cell of the glomerular filtration barrier, and possesses unique architectural and signaling properties guided by the expression of key podocyte specific proteins. How these cellular features are damaged by the diabetic milieu is unclear, but what is becoming increasingly clear is that damage to the podocyte is a central event in DN. Here we present accumulating evidence that insulin action itself is important in podocyte biology, and may be deranged in the pathomechanism of early DN. This introduces a rationale for therapeutic intervention to improve podocyte insulin sensitivity early in the presentation of DN.     

The Notch pathway regulates KLF4 in podocyte injury induced by high glucose

International Journal of Diabetes in Developing Countries - Diabetic nephropathy (DN) is a common complication of diabetes. The Notch pathway plays an important role in podocyte injury and...     

Role of angiotensin II in the development of nephropathy and podocytopathy of diabetes

Diabetic kidney disease is the leading cause of end-stage renal disease worldwide. Podocytes are highly differentiated, pericyte-like cells that are essential for normal function of the kidney filter. Loss of podocytes is a hallmark of progressive kidney diseases including diabetic nephropathy. Podocytes are a direct target for angiotensin II - mediated injury by altered expression and distribution of podocyte proteins. Additionally, angiotensin II promotes podocyte injury indirectly by increasing calcium influx and production of reactive oxygen species. Notwithstanding the convincing rationale for angiotensin II blockade as a treatment modality, the incidence of diabetes-related end stage renal disease has increased steadily despite widespread use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Recently published clinical trials have rekindled a debate on the safety and efficacy of dual blockade of the renin-angiotensin system (RAS). This review summarizes the rationale for blockade of angiotensin II as a therapeutic target in treating diabetic kidney disease, including the critical role played by podocytes. Recent relevant clinical trials on the role of RAS blockade in the treatment of diabetic kidney disease are discussed.     

糖尿病糖脂代谢紊乱与足细胞损害的实验研究

目的　观察糖脂代谢紊乱对糖尿病大鼠肾小球滤过屏障外层足细胞的影响 ,以探讨糖尿病肾病的发病机制。方法　采用链脲佐菌素诱导糖尿病大鼠模型 ,喂养 5周后 ,测定血糖、糖化血红蛋白、甘油三酯、总胆固醇、血肌酐、尿素氮和尿白蛋白排泄率 ,应用免疫组化检测肾小球足细胞损伤标志蛋白 -desmin的表达 ,同时利用透射电子显微镜观察肾小球足细胞超微结构。结果　糖尿病大鼠血糖、糖化血红蛋白、总胆固醇、血肌酐、尿素氮、尿白蛋白排泄率水平明显升高 (P <0 .0 5 ) ,肾小球内desmin蛋白表达上调 ,足细胞部分足突融合 ;同时 ,两组间血甘油三酯水平无显著性差异 (P >0 .0 5 )。结论　糖脂代谢紊乱可导致糖尿病大鼠肾小球滤过屏障外层足细胞明显损害 ,尿白蛋白排泄率增加 ,这可能是糖尿病肾脏损害、蛋白尿出现的机制之一