Collagen COL4A3 knockout: A mouse model for autosomal Alport syndrome
Collagen COL4A3 knockout: A mouse model for autosomal Alport syndrome
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DOI：
10.1101/gad.10.23.2981
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发表时间：
1996-12-01
影响因子：
10.5
通讯作者：
Samuelson, GC
中科院分区：
文献类型：
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作者：
Cosgrove, D;Meehan, DT;Samuelson, GC
产生了Alport综合征常染色体形式的小鼠模型。这些小鼠发展为进行性肾小球肾炎，伴有微量血尿和蛋白尿，与人类疾病一致。末期肾病疾病在近似14周龄时发展。TEM分析肾小球基底膜（GEM）在发展过程中的肾脏病理显示局灶性多层增厚和变薄开始在外部毛细血管环路在4周和蔓延整个GEM的8周。到14周，一半的肾小球纤维化，毛细血管塌陷。GBM的免疫荧光分析显示IV型胶原α-3、α-4和α-5链的缺失以及α-1和α-2链的持续存在（这些链通常定位于系膜基质）。使用对胶原蛋白链特异的探针的北方印迹分析说明在敲除中不存在COL 4A 3，而其余链的mRNA不变。在受影响动物的GBM中观察到纤连蛋白、硫酸乙酰肝素蛋白聚糖、层粘连蛋白-1和巢蛋白的积累。的时间和空间模式的积累是一致的增厚的GBM观察到的TEM。因此，这些基底膜相关蛋白的表达可能参与Alport肾病发病机制的进展。编码基底膜相关蛋白的mRNA水平在7周时没有变化。
A mouse model for the autosomal form of Alport syndrome was produced. These mice develop a progressive glomerulonephritis with microhematuria and proteinuria, consistent with the human disease. End-stage renal. disease develops at similar to 14 weeks of age. TEM analysis of the glomerular basement membranes (GEM) during development of renal pathology revealed focal multilaminated thickening and thinning beginning in the external capillary loops at 4 weeks and spreading throughout the GEM by 8 weeks. By 14 weeks, half of the glomeruli were fibrotic with collapsed capillaries. Immunofluorescence analysis of the GBM showed the absence of type IV collagen alpha-3, alpha-4, and alpha-5 chains and a persistence of alpha-1 and alpha-2 chains (these chains normally localize to the mesangial matrix). Northern blot analysis using probes specific for the collagen chains illustrate the absence of COL4A3 in the knockout, whereas mRNAs for the remaining chains are unchanged. An accumulation of fibronectin, heparan sulfate proteoglycan, laminin-1, and entactin was observed in the GBM of the affected animals. The temporal and spatial pattern of accumulation was consistent with that for thickening of the GBM as observed by TEM. Thus, expression of these basement membrane-associated proteins may be involved in the progression of Alport renal disease pathogenesis. The levels of mRNAs encoding the basement membrane-associated proteins at 7 weeks were unchanged.