The Gne M712T Mouse as a Model for Human Glomerulopathy
The Gne M712T Mouse as a Model for Human Glomerulopathy
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DOI：
10.1016/j.ajpath.2011.12.023
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发表时间：
2012-04-01
影响因子：
6
通讯作者：
Huizing, Marjan
中科院分区：
文献类型：
--
作者：
Kakani, Sravan;Yardeni, Tal;Huizing, Marjan
病理性肾小球低唾液酸化与某些原因不明的肾小球病有关，包括微小病变肾病、膜性肾小球肾炎和伊加肾病。我们研究了我们以前建立的小鼠模型携带唾液酸生物合成的关键酶，N-乙酰葡糖胺2-差向异构酶/N-乙酰甘露糖胺激酶的纯合突变。突变小鼠在出生后第3天（P3）之前死于严重肾小球病，伴有足细胞消失和由于低唾液酸化导致的节段性肾小球基底膜分裂。给予唾液酸前体N-乙酰甘露糖胺（ManNAc）可改善P3后突变幼仔的唾液酸化和存活率。我们确定了肾小球病的发病在胚胎阶段。一个凝集素组，区分正常唾液酸化和低唾液酸化聚糖，使用WGA，SNA，PNA，Jacalin，HPA和VVA，表明突变小鼠中主要O-连接糖蛋白的肾小球低唾液酸化。肾小球糖蛋白nephrin和podocalyxin在这种独特的小鼠模型中被低唾液酸化。ManNAc治疗似乎改善了突变小鼠的低唾液酸化状态，表明与野生型小鼠相似的凝集素组织化学模式，与未治疗的突变小鼠相比，nephrin和podocalyxin的唾液酸化改善，以及白蛋白尿减少。这些发现表明，我们的凝集素面板分类人类肾脏标本的肾小球唾液酸化状态的基础上的应用。此外，ManNAc处理的小鼠中肾小球结构的部分恢复突出了ManNAc作为受肾小球低唾液酸化病症影响的人类的潜在治疗。(Am J Pathol 2012，180：1431-1444; DOI：10.1016/j.ajpath.2011.12.023）
Pathological glomerular hyposialylation has been implicated in certain unexplained glomerulopathies, including minimal change nephrosis, membranous glomerulonephritis, and IgA nephropathy. We studied our previously established mouse model carrying a homozygous mutation in the key enzyme of sialic acid biosynthesis, N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Mutant mice died before postnatal day 3 (P3) from severe glomerulopathy with podocyte effacement and segmental glomerular basement membrane splitting due to hyposialylation. Administration of the sialic acid precursor N-acetylmannosamine (ManNAc) led to improved sialylation and survival of mutant pups beyond P3. We determined the onset of the glomerulopathy in the embryonic stage. A lectin panel, distinguishing normally sialylated from hyposialylated glycans, used WGA, SNA, PNA, Jacalin, HPA, and VVA, indicating glomerular hyposialylation of predominantly O-linked glycoproteins in mutant mice. The glomerular glycoproteins nephrin and podocalyxin were hyposialylated in this unique murine model. ManNAc treatment appeared to ameliorate the hyposialylation status of mutant mice, indicated by a lectin histochemistry pattern similar to that of wild-type mice, with improved sialylation of both nephrin and podocalyxin, as well as reduced albuminuria compared with untreated mutant mice. These findings suggest application of our lectin panel for categorizing human kidney specimens based on glomerular sialylation status. Moreover, the partial restoration of glomerular architecture in ManNAc-treated mice highlights ManNAc as a potential treatment for humans affected with disorders of glomerular hyposialylation. (Am J Pathol 2012, 180:1431-1444; DOI: 10.1016/j.ajpath.2011.12.023)