Minimal change disease as a modifiable podocyte paracrine disorder
Minimal change disease as a modifiable podocyte paracrine disorder
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DOI：
10.1093/ndt/gfr124
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发表时间：
2011-06-01
影响因子：
6.1
通讯作者：
Reiser, Jochen
中科院分区：
文献类型：
--
作者：
Wei, Changli;Reiser, Jochen
肾病综合征是一种常见疾病，可追溯到世纪，已知影响儿童和成人[1]。原发性肾病综合征有三种不同的组织学变异，微小病变（MCD），局灶节段性肾小球硬化（FSGS）和膜性肾病（MN），这是罕见的儿童。在临床实践中，约95%的MCD患者对皮质类固醇有反应，而大多数FSGS患者对类固醇治疗耐药[2]。在病理生理学上，肾病综合征的特征性特征群源于肾小球毛细血管壁的选择性渗透屏障的原发性改变，允许增加进入尿液的血浆蛋白的损失[1，3]。在形态学上，肾滤过屏障由三层组成，即肾小球有孔内皮细胞（GEC）、肾小球基底膜（GBM）和足细胞及其足突[3]。GEC被由带负电荷的糖萼组成的表面层覆盖，从而有助于过滤器的电荷选择性[3，4]。GBM是一种细胞外基质胶，有助于形成肾小球毛细血管壁的结构，并提供大量负电荷[3，4]。足细胞已被深入研究，以更好地定义这些细胞在健康和疾病期间的反应[3，4]。尽管对肾脏超滤屏障的认识取得了重大进展，但肾病综合征的分子机制及其与特定实体的关系仍不清楚。这是一个特别困难的问题，因为肾小球内的初始结构变化是不可区分的，并且通常受益于其他临床反应，例如类固醇的成功试验，其将MCD指向FSGS或MN。在最近一期的《自然医学》中，Clement et al. [5]确定了血管生成素样蛋白4（ANGPTL4）在糖皮质激素敏感性肾病综合征中的作用。ANGPTL4属于一组蛋白质，其在结构上类似于血管生成因子血管生成素，但血管生成素样蛋白质不与血管生成素受体Tie 2或相关蛋白质Tie 1结合，因此是孤儿配体[6]。ANGPTL4与高脂血症[7]和肿瘤转移[8]有关。在人类中，ANGPTL4广泛表达，但特别是在肝脏和脂肪组织中富集[9]。由于高脂血症是肾病综合征的主要特征之一，Clement et al. [5]探索了ANGPTL4在MCD中的表达，并发现其在MCD实验模型以及人MCD中的血清以及足细胞中上调。在遗传模型的帮助下，他们发现没有内源性ANGPTL4的小鼠受到脂多糖（LPS）诱导的蛋白尿的保护。相反，在足细胞中过表达ANGPTL4的大鼠出现大规模白蛋白尿、GBM电荷损失以及足细胞足突消失[5]，表明ANGPTL4在MCD中的致病作用。Clement等人进行的这项新研究在几个方面对肾脏病学家和肾脏研究人员特别感兴趣。首先，ANGPTL4表达似乎对糖皮质激素敏感。使用类固醇治疗肾病综合征已实践多年，但遗憾的是对其工作机制知之甚少[10]。值得注意的是，Clement et al. [5]报道了ANGPTL4的表达在糖皮质激素处理后降低，表明ANGPTL4可以被认为是体内足细胞中的类固醇敏感性靶标。需要更多的研究来探索足细胞ANGPTL4是否是类固醇的直接靶点。其次，Clement等人确定了ANGPTL4对...
Nephrotic syndrome is a common illness dating back to the 15th century and known to affect both children and adults [1]. There are three distinct histological variants of primary idiopathic nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN), which is rare in children. In clinical practice,∼ 95% MCD patients respond to corticosteroids, while most FSGS patients are resistant to steroids therapy [2]. Pathophysiologically, the constellation of features that characterize nephrotic syndrome stems from primary alterations of the permselectivity barrier of the glomerular capillary wall, allowing increasing loss of plasma proteins into the urine [1, 3]. Morphologically, the renal filtration barrier consists of three layers, the glomerular fenestrated endothelial cells (GECs), the glomerular basement membrane (GBM) and podocytes with their foot processes [3]. The GECs are covered by a surface layer made of negatively charged glycocalyx, thus contributing to the charge selectivity of the filter [3, 4]. The GBM is an extacellular matrigel that helps to form the structure of the glomerular capillary wall and also provide a heavily negative charge [3, 4]. Podocytes have been intensely studied to better define how these cells react during health and disease [3, 4]. Despite significant progress in understanding the kidney ultrafiltration barrier, the molecular mechanisms of nephrotic syndrome and how it relates to its specific entities are still unclear. This is a particularly difficult problem as the initial structural changes inside the glomerulus are indistinguishable and often benefit from additional clinical responses such as a successful trial of steroids which rather points to MCD as supposed to FSGS or MN. In a recent issue of Nature Medicine, Clement et al.[5] identified a role of angiopoietin-like-4 (ANGPTL4) in glucocorticoid-sensitive nephrotic syndrome. ANGPTL4 belongs to a group of proteins, that are structurally similar to the angiogenic factors angiopoietins but angiopoietinslike proteins do not bind to either the angiopoietin receptor Tie2 or the related protein Tie1 and thus are orphan ligands [6]. ANGPTL4 has been implicated in hypertriglyceridemia [7] and tumor metastasis [8]. In human, ANGPTL4 is ubiquitously expressed but particularly enriched in the liver and adipose tissue [9]. Prompted by the fact that hyperlipidemia is one of the major features of nephrotic syndrome, Clement et al.[5] explored the expression of ANGPTL4 in MCD and found it upregulated in the serum as well as in podocytes in experimental models of MCD as well as human MCD. With the help of genetic models, they found that mice without endogenous ANGPTL4 are protected from lipopolysaccharide (LPS)-induced proteinuria. In contrast, rats that overexpress ANGPTL4 in podocytes develop large-scale albuminuria, loss of GBM charge as well as podocyte foot processes effacement [5], suggesting a causative role of ANGPTL4 in MCD. This novel study performed by Clement et al. is particularly interesting to both nephrologists and renal researchers in several aspects. Firstly, ANGPTL4 expression seems glucocorticoid sensitive. The use of steroids in treatment of nephrotic syndrome has been in practice for many years, but unfortunately little is know about its working mechanisms [10]. Notably, Clement et al.[5] reported the expression of ANGPTL4 to be reduced after glucocorticoid treatment, suggesting that ANGPTL4 can be considered a steroid sensitive target in podocytes in vivo. More studies are warranted to explore if podocyte ANGPTL4 is a direct target for steroids. Secondly, Clement et al. identified the effect of ANGPTL4 on …