肾小球足细胞生理功能与致损伤因素

近年来对足细胞在维持肾小球滤过屏障和肾功能的作用研究逐步深入.研究证实,足细胞是多种肾小球疾病免疫或非免疫损伤的靶标,多种类型的肾小球疾病均特征性地表现为足细胞异常.足细胞损伤往往会引起肾小球滤过膜结构和功能异常,从而导致蛋白尿的产生.深入认识足细胞的生理功能及致损伤因素,对于临床有效防治肾小球损伤性疾病有重要意义.     

mTOR与肾小球疾病

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种进化上十分保守的蛋白激酶,催化特定的底物来调节蛋白翻译、细胞生长、增殖、自噬等基本生理活动,在肿瘤、糖尿病、多种肾脏病中起重要调节作用.多数肾小球疾病由足细胞损伤、滤过屏障受损引起.已有研究证实mTOR与足细胞损伤有关,但具体调节机制尚不明确.该文对mTOR激酶的调节机制以及在肾小球疾病发生发展中的作用进行综述,为认识肾小球疾病的发病机制提供新的思路.     

TRPC6与肾脏疾病关系的研究进展

瞬时受体电位阳离子通道蛋白6（TRPC6）是由TRPC6基因编码的瞬时受体超家族成员之一,在人体内各组织或器官广泛表达,在肾小球足细胞也有表达。TRPC6与podocin、nephrin、ACTN4及CD2AP等多种裂孔隔膜（SD）蛋白相互作用共同维系肾小球足细胞的结构及功能。多因素作用导致肾小球足细胞损伤引起SD的足突融合是肾脏疾病最主要的形态学改变。该文就TRPC6生物学功能及其对肾脏疾病的影响作一简述。     

足细胞损伤与肾脏疾病的研究进展

近年来足细胞成为肾脏病学的研究热点之一.足细胞损伤在肾小球疾病的发生发展过程中起着关键性作用,对足细胞分子生物学和病理学的深入认识将为相关肾病的防治提供新的思路.该文就足细胞生物学、足细胞损伤与肾小球疾病及其干预的研究进展作一综述.     

西罗莫司靶蛋白信号传导通路与肾脏足细胞自噬的研究进展

近些年来,随着人们对肾脏足细胞自噬研究的不断深入,越来越多的自噬信号通路被发现.其中,以西罗莫司靶蛋白(mTOR)介导的自噬信号传导通路为自噬治疗靶点的方案逐渐成为研究热点.很多研究证明,mTOR信号传导通路在肾小球足细胞自噬的发生发展中起重要作用,mTOR是肾小球足细胞自噬调控的重要信号通路,也是肾小球足细胞营养状态的感受器.目前根据自噬调控机制的不同,国际上统一将自噬调控机制分为依赖mTOR途径的自噬调控机制和非依赖mTOR途径的自噬调控机制.肾小球足细胞mTOR的上下游信号传导通路较为复杂,mTOR作为生长因子、胰岛素、氨基酸等物质的感受器,对足细胞生长发育起重要的调节作用.因此,mTOR活化介导的自噬在肾小球足细胞损伤中起重要作用,mTOR信号传导通路可能成为干预肾小球足细胞损害的一种潜在治疗方法.     

Beclin-1在肾小球足细胞自噬调控中的作用

自噬是一个发生在真核细胞中由细胞初级溶酶体处理内源性底物的一系列生化过程,其主要作用是清除和降解自身受损的细胞器及多余的生物大分子,并利用降解产物提供能量和重建细胞结构,在维持细胞稳态和细胞生命活动等方面起重要作用.近年来,研究发现肾小球足细胞的自噬活性水平与足细胞的损伤和蛋白尿的发生发展有关.自噬在肾小球足细胞中起到的调控作用成为对抗足细胞损伤的研究热点,其中自噬相关基因Beclin-1在自噬调控中的作用更是引起了广泛关注.现就近年来关于Beclin-1在足细胞自噬调控中作用的相关研究进行综述.     

nephrin与肾脏疾病

nephrin为肾小球足突细胞裂孔隔膜的重要组成成分,在维持肾小球过滤屏障方面起关键作用,而且在细胞-细胞间黏附和/或信号传导方面亦起作用。目前已证实,编码nephrin蛋白的基因NPHS1的突变为先天性肾病综合征的病因。人类蛋白尿相关的肾小球疾病可能与nephrin的异常有关。关于nephrin与人类蛋白尿相关的肾小球疾病的研究,可能对肾小球疾病蛋白尿产生机制的认识及其治疗开辟新的途径。     

多功能蛋白p62在肾脏疾病中的研究进展

p62是机体内普遍存在的一种含有6个结构域的多功能蛋白。p62参与选择性自噬降解泛素化底物,并已成为监测细胞自噬的重要生物标志物。除此之外,p62还参与氧化应激、细胞营养感知、细胞凋亡和代谢重编程等众多生物学过程。p62的表达受TFEB等转录因子的调控。既往研究发现p62基因突变与神经系统等疾病密切相关,近来还发现p62参与维护肾小球足细胞、系膜细胞和肾小管上皮细胞的正常功能。基于p62蛋白功能的多样性与重要性,该蛋白有望成为治疗肾脏疾病的靶点之一。     

nephrin与肾脏疾病

nephrin为肾小球足突细胞裂孔隔膜的重要组成成分，在维持肾小球过滤屏障方面起关键作用，而且在细胞－细胞间黏附和／或信号传导方面亦起作用。目前已证实，编码nephrin蛋白的基因NPHS1的突变为先天性肾病综合征的病因。人类蛋白尿相关的肾小球疾病可能与nephrin的异常有关。关于nephrin与人类蛋白尿相关的肾小球疾病的研究，可能对肾小球疾病蛋白尿产生机制的认识及其治疗开辟新的途径。     

Th17、Treg及足细胞损伤与原发性肾小球疾病研究进展

近年来辅助性T细胞17(T helper cell,Th17)、调节性T细胞(regulatory T cell,Treg)、足细胞损伤在原发性肾小球疾病发病机制中的作用受到广泛关注。 Th17细胞通过分泌IL-17等细胞因子,具有招募中性粒细胞和巨噬细胞到感染部位的功能;Treg细胞具有免疫调节功能,介导免疫耐受,保护机体免受炎症损伤。 Th17细胞比例升高、Treg细胞比例下降引起的失衡在原发性肾小球疾病的发病机制及病情进展中可能起到重要作用。足细胞作为肾小球滤过屏障的重要组成部分,近年来成为研究热点。深入探讨Th17、Treg以及足细胞损伤与原发性肾小球疾病的关系,可为原发性肾小球疾病的防治寻找新的靶点提供依据。     

The intermediate filament nestin is highly expressed in normal human podocytes and podocytes in glomerular disease.

The intermediate protein nestin is expressed in proliferating embryonic tissues and adult tissues undergoing repair. Recently this protein been identified in rodent podocytes. Its role in this cell is unknown, since podocytes are believed to be terminally differentiated and nondividing. We report the first study of nestin in human kidney. Nestin expression in normal mature human glomeruli was confined to podocytes. In developing kidney, nestin was detected in metanephric blastema and in podocytic cells at all stages of glomerular development. Nestin co-localized with vimentin but not with actin or heavy chain myosin IIA, using a mouse podocyte cell line. Knockdown of nestin in a murine podocyte cell line failed to produce any obvious phenotypic change or alteration in vimentin distribution but was associated with increased cell cycling. A survey of glomerular diseases failed to identify any condition lacking nestin, indicating that the protein is critical for some aspect of podocyte function. Perhaps through an association with vimentin, nestin serves to bolster the mechanical strength of these cells that experience high tensile stress during glomerular filtration. Nestin was also expressed in podocytes that are reported to be 'dysregulated' (lacking podocyte markers). Thus, nestin has a potential as a reliable podocyte marker, even for podocytes that are not completely differentiated (for example, during development) or 'dedifferentiated' in glomerular disease.     

Genetics of the nephrotic syndrome

There are a large number of glomerular diseases that may be responsible for a nephrotic syndrome, the most frequent in childhood being minimal change disease. In the past few years, the molecular genetic basis of several conditions that may cause a nephrotic syndrome have been identified. Denys-Drash syndrome and Frasier syndrome are related diseases caused by mutations in the WT1 gene. Familial forms of idiopathic nephrotic syndrome with focal and segmental glomerular sclerosis/hyalinosis have been identified with an autosomal dominant or recessive mode of inheritance and linkage analysis have allowed to localize several genes on chromosomes 1, 11 and 17. The gene responsible for the Finnish type congenital nephrotic syndrome has been identified. This gene, named NPHS1, codes for nephrin, which is located at the slit diaphragm of the glomerular podocytes and is thought to play an essential role in the normal glomerular filtration barrier.     

蛋白尿的发生机制研究进展

蛋白尿的主要发生机制是肾小球滤过增加和（或）肾小管重吸收障碍。近年来,对肾小球滤过屏障研究取得显著进展,内皮细胞表层和足细胞下间隙成为肾小球滤过屏障新组分,发现越来越多的足细胞分子与蛋白尿关系密切,主导或者参与了肾小球疾病的发生。     

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??Proteinuria occurs mainly due to increased filtration of plasma proteins through glomerular capillary wall and/or incapability of renal tubular reabsorption of small molecular proteins. Significant advances have been made in study on glomerular filtration barrier in recent years. Now endothelial surface layer and subpodocyte space have been accepted as new layers of whole glomerular filtration barrier??and more and more podocyte molecules have been found to play a causative role or participate in the occurrence of proteinuria.     

阿霉素肾病大鼠中肾小球nephrin表达与氧化应激反应的关系

目的：氧化和抗氧化失衡可能是肾病综合征产生大量蛋白尿的原因之一,而肾小球裂隙膜分子nephrin在维持肾小球滤过屏障功能中起着重要作用。因此该实验初步探讨阿霉素肾病大鼠肾小球裂隙膜分子nephrin表达与氧化应激反应的关系,以及泼尼松和维生素E对阿霉素大鼠肾损伤保护作用的机制。方法：尾静脉单次注射阿霉素5 mg/kg建立肾病发病过程中的氧化应激模型,并增加泼尼松和维生素E干预。应用化学比色法检测肾皮质氧化应激指标变化,应用免疫组织化学技术观察肾小球裂隙膜分子nephrin表达变化,并对两者进行相关性分析。结果：①肾病组大鼠肾皮质丙二醛（MDA）含量及24 h尿蛋白排泄量高于正常对照组,超氧化物歧化酶（SOD）和总抗氧化能力（T-AOC）活性低于正常对照组。与肾病组相比,泼尼松和维生素E干预组从14 d开始尿蛋白排泄量明显减少,直到28 d（P<0.05）。维生素E干预组肾皮质MDA含量较肾病28 d组下降,SOD、T-AOC活性较肾病28 d组升高。②正常对照组大鼠nephrin沿肾小球基底膜呈深褐色连续线性分布;肾病组随时间的延长深褐色连续线性分布向浅褐色短线条状或点状分布转化;泼尼松和维生素E干预组减轻了nephrin分子的异常改变;量化分析显示,肾病组肾小球nephrin阳性表达含量明显低于正常对照组,泼尼松及维生素E干预组肾小球nephrin阳性表达含量较肾病组增加。③肾小球nephrin蛋白阳性表达含量与肾皮质MDA含量呈负相关,与肾皮质SOD和T-AOC活性呈正相关。结论：肾小球裂隙膜分子nephrin表达减少与氧化应激反应密切相关;泼尼松和维生素E对阿霉素肾病大鼠肾损伤有保护作用。［中国当代儿科杂志,2009,11（1）：56-60］     

Renal hyperperfusion injury resulting in transient proteinuria post renal artery angioplasty for fibromuscular dysplasia

Renovascular hypertension (RVH) can be treated utilizing medical, surgical or endovascular techniques. We present a case in which severe exacerbation of pre-existing proteinuria followed percutaneous transluminal angioplasty of a highly stenotic renal artery to relieve RVH caused by fibromuscular dysplasia. We propose that the worsening proteinuria post-angioplasty was caused by a transient renal hyperperfusion injury that overcame the glomerular autoregulatory mechanisms, thereby leading to raised intraglomerular pressures and loss of proteins through the glomerular filtration barrier until the vascular autoregulatory ability of the glomeruli was successfully re-established.     

Beta 2 microglobulin in the serum as a parameter of glomerular kidney function in the first days of life

Though serum creatinine is a very reliable parameter for predicting glomerular filtration rate in infancy, this does not apply to the first hours and days of life. As there is no placental barrier for creatinine, serum creatinine at birth reflects maternal renal function at the moment of delivery and, during the first days of life, establishment of the steady state condition between creatinine serum level and actual infantile glomerular filtration rate. Serum creatinine levels of cord blood and maternal blood in term and preterm infants of 25-42 weeks gestational age are almost identical (maternal blood 0.82 +/- 0.34 mg-%, cord blood 0.87 +/- 0.34 mg-%, n = 77, r = 0.94), whereas there is no correlation between maternal and infantile beta 2-microglobulin concentrations (maternal blood 2.1 + 1 mg/1, cord blood 3.3 +/- 0.6 mg/l, n = 78, r = 0.05). There is no free diaplacental exchange for this low molecular weight protein. The determination of cord blood beta 2-microglobulin levels therefore predicts the newborn's renal function independently of the mother's. It is possible to differentiate between prenatal and perinatal genesis of renal damage in case of renal failure in the newborn, and to study the elimination of creatinine preloading in maternal renal insufficiency. Although we are not yet able to give an exact quantitative prediction of glomerular filtration rate by determining beta 2-microglobulin we believe it to be the best parameter of glomerular renal function in this age-group.