Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo.
Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo.
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DOI：
10.1038/ki.2013.281
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发表时间：
2014-02
影响因子：
19.6
通讯作者：
McCarthy KJ
中科院分区：
文献类型：
--
作者：
Sugar T;Wassenhove-McCarthy DJ;Esko JD;van Kuppevelt TH;Holzman L;McCarthy KJ
硫酸乙酰肝素蛋白聚糖已被证明可以调节足细胞粘附到肾小球基底膜上以及肾小球基底膜上的蒂组织。最近的研究表明，足突消失发生在突变小鼠模型中，其足细胞不能组装硫酸乙酰肝素糖胺聚糖链。这项研究，进一步完善，探讨了乙酰肝素N-硫酸化对足细胞行为的作用。开发了一种新的突变小鼠（Ndst 1-/-），具有足细胞特异性缺失的NDST 1，负责硫酸乙酰肝素链的N-硫酸化的酶。具有这种突变的足细胞具有足突消失和与Bowman囊的异常粘附。虽然肾小球肥大确实发生在突变动物的肾脏中，但未观察到系膜扩张。乙酰肝素N-硫酸化的缺乏不影响聚集蛋白或串珠蛋白聚糖核心蛋白的表达。N-硫酸化的丧失并不导致显著的蛋白尿，但白蛋白/肌酐比值的增加与近端小管中扩大的溶酶体的发展一致。因此，尽管Ndst 1-/-小鼠的肾表型是轻度的，但数据显示乙酰肝素链N-硫酸化在足细胞组织中起关键作用。
Heparan sulfate proteoglycans have been shown to modulate podocyte adhesion to- and pedicel organization on- the glomerular basement membrane. Recent studies showed that foot process effacement developed in a mutant mouse model whose podocytes were unable to assemble heparan sulfate glycosaminoglycan chains. This study, a further refinement, explored the role of heparan N-sulfation on podocyte behavior. A novel mutant mouse (Ndst1-/-) was developed, having podocyte-specific deletion of NDST1, the enzyme responsible for N-sulfation of heparan sulfate chains. Podocytes having this mutation had foot process effacement and abnormal adhesion to Bowman's capsule. Although glomerular hypertrophy did develop in the kidneys of mutant animals, mesangial expansion was not seen. The lack of heparan N-sulfation did not affect the expression of agrin or perlecan proteoglycan core proteins. Loss of N-sulfation did not result in significant proteinuria, but the increase in the albumin/creatinine ratio was coincident with the development of the enlarged lysosomes in the proximal tubules. Thus, although the renal phenotype of the Ndst1-/- mouse is mild, the data show that heparan chain N-sulfation plays a key role in podocyte organization.