Laminin compensation in collagen α3(IV) knockout (Alport) glomeruli contributes to permeability defects

被引:51
作者
Abrahamson, Dale R.
Isom, Kathryn
Roach, Eileen
Stroganova, Larysa
Zelenchuk, Adrian
Miner, Jeffrey H.
John, Patricia L. St.
机构
[1] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Kansas City, KS 66160 USA
[2] Washington Univ, Dept Internal Med, Div Renal, St Louis, MO 63130 USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2007年 / 18卷 / 09期
关键词
D O I
10.1681/ASN.2007030328
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Alport disease is caused by mutations in genes encoding the alpha 3, alpha 4, or alpha 5 chains of type IV collagen, which form the collagenous network of mature glomerular basement membrane (GBM). In the absence of alpha 3, alpha 4, alpha 5 (IV) collagen, alpha 1, alpha 2 (IV) collagen persists, which ordinarily is found only in GBM of developing kidney. In addition to dysregulation of collagen IV, Alport GBM contains aberrant laminins, which may contribute to the progressive GBM thickening and splitting, proteinuria, and renal failure seen in this disorder. This study sought to characterize further the laminin dysregulation in collagen alpha 3(IV) knockout mice, a model of Alport disease. With the use of confocal microscopy, laminin alpha 1 and alpha 5 abundance was quantified, and it was found that they co-distributed in significantly large amounts in areas of GBM thickening. In addition, labeling of entire glomeruli for laminin alpha 5 was significantly greater in Alport mice than in wild-type siblings. Reverse transcriptase-PCR from isolated glomeruli demonstrated significantly more laminin alpha 5 mRNA in Alport mice than in wild-type controls, indicating upregulated transcription of Lama5. For testing glomerular barrier function, ferritin was injected into 2-wk-old Alport and control mice, and GBM was examined by electron microscopy. Highest ferritin levels were seen in Alport GBM thickenings beneath effaced podocyte foot processes, but morphologically normal GBM was significantly permeable as well. We concluded that (1) ultrastructurally normal Alport GBM residing beneath differentiated podocyte foot processes is inherently and abnormally permeable, and (2) upregulation of Lama5 transcription and concentration of laminin alpha 1 and alpha 5 within Alport GBM thickenings contribute to abnormal permeabilities.
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页码:2465 / 2472
页数:8
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