研究人员发现，在肾脏疾病中，糖蛋白血管生成素样蛋白-4抗体(Angptl4)的分泌发挥了作用，新成果发表在12月在线出版的Nature Medicine期刊上，并有望成为治疗某种肾脏疾病的途径。

足状突细胞是肾脏中参与血液过滤的关键细胞。这种细胞功能的紊乱会导致损害肾脏的肾病综合征，肾脏将血液中大量的蛋白质泄漏到尿液中。Sumant  Chugh和同事指出，由足状突细胞所产生的Angptl4过多分泌会导致这种情况的发生。

他们发现，在通过实验引导的肾病综合征的小鼠体内，Angptl4信使RNA和蛋白质在足状突细胞中被高度调控，与人类患者体内取出的生物切片情形相似。他们还指出，通过基因改造而让Angptl4在小鼠和老鼠体内过度表达会引发肾病综合征的发生，而Angptl4被剔除的小鼠则不会发生这种疾病。

然而，科学家们目前还不完全清楚Angptl4的过度表达如何导致了肾病综合征，但Chugh的小组发现，大量过多分泌的Angptl4被足状突细胞不恰当地修饰。这种结果改变了蛋白质的电荷性，并最终改变了肾脏过滤器中的细胞外基质的净电荷，导致其功能的紊乱。

研究人小组的发现支持了该假说，他们用唾液酸前体喂养过度表达Angptl4的小鼠，结果大大提高了分泌Angptl4的电荷，帮助改善了它们的肾脏疾病。

原文出处：

Nature Medicine   doi:10.1038/nm.2261

Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome

Lionel C Clement,Carmen Avila-Casado,Camille Macé,Elizabeth Soria,Winston W Bakker,Sander Kersten& Sumant S Chugh

The main manifestations of nephrotic syndrome include proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. Common causes of nephrotic syndrome are diabetic nephropathy, minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) and membranous nephropathy. Among the primary glomerular diseases, MCD is usually sensitive to glucocorticoid treatment, whereas the other diseases show variable responses1. Despite the identification of key structural proteins in the glomerular capillary loop which may contribute to defects in ultrafiltration, many of the disease mechanisms of nephrotic syndrome remain unresolved. In this study, we show that the glomerular expression of angiopoietin-like-4 (Angptl4), a secreted glycoprotein, is glucocorticoid sensitive and is highly upregulated in the serum and in podocytes in experimental models of MCD and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range, and selective, proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, whereas transgenic expression specifically in the adipose tissue (aP2-Angptl4) resulted in increased circulating Angptl4, but no proteinuria. Angptl4?/? mice that were injected with lipopolysaccharide (LPS) or nephritogenic antisera developed markedly less proteinuria than did control mice. Angptl4 secreted from podocytes in some forms of nephrotic syndrome lacks normal sialylation. When we fed the sialic acid precursor N-acetyl-D-mannosamine (ManNAc) to NPHS2-Angptl4 transgenic rats it increased the sialylation of Angptl4 and decreased albuminuria by more than 40%. These results suggest that podocyte-secreted Angptl4 has a key role in nephrotic syndrome.