Albumin contributes to kidney disease progression in Alport syndrome
Albumin contributes to kidney disease progression in Alport syndrome
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DOI：
10.1152/ajprenal.00456.2015
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发表时间：
2016-07-01
影响因子：
4.2
通讯作者：
Miner, Jeffrey H.
中科院分区：
文献类型：
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作者：
Jarad, George;Knutsen, Russell H.;Miner, Jeffrey H.
Alport综合征是一种家族性肾脏疾病，由肾小球基底膜的IV型胶原网络缺陷引起。缺乏胶原蛋白α（3）α（4）α（5）（IV）改变肾小球基底膜的形态和功能，使其漏入白蛋白和其他血浆蛋白。滤过白蛋白被认为是在晚期Alport综合征中观察到的肾小球和肾小管损伤的原因。为了直接研究白蛋白在Alport综合征疾病进展中的作用，我们产生了白蛋白敲除（Alb（-/-））小鼠，用作去除作为肾脏疾病组成部分的白蛋白尿的工具。缺乏白蛋白的小鼠是健康的，与对照同窝小鼠没有区别，尽管它们发展为高胆固醇血症。在Alb（+/-）小鼠中观察到血脂异常，其显示正常血浆白蛋白浓度的一半。将Alb突变小鼠与作为人类Alport综合征模型的胶原蛋白-α（3）（IV）敲除（Col 4a 3（-/-））小鼠交配。在Col 4a 3（-/-）; Alb（-/-）小鼠中缺乏循环和过滤的白蛋白导致肾脏疾病结局显著改善，因为这些小鼠的寿命比Col 4a 3（-/-）; Alb（+/+）和Col 4a 3（-/-）; Alb（+/-）小鼠长64%，尽管血压和血清甘油三酯水平相似。进一步的研究表明，白蛋白的缺乏与转化生长因子-β（1）信号传导减少以及肾小管间质、肾小球和足细胞病理学减少相关。我们的结论是，过滤白蛋白是有害的肾细胞在Alport综合征，也许在其他蛋白尿性肾脏疾病，包括糖尿病肾病。
Alport syndrome is a familial kidney disease caused by defects in the collagen type IV network of the glomerular basement membrane. Lack of collagen alpha(3)alpha(4)alpha(5)(IV) changes the glomerular basement membrane morphologically and functionally, rendering it leaky to albumin and other plasma proteins. Filtered albumin has been suggested to be a cause of the glomerular and tubular injuries observed at advanced stages of Alport syndrome. To directly investigate the role that albumin plays in the progression of disease in Alport syndrome, we generated albumin knockout (Alb(-/-)) mice to use as a tool for removing albuminuria as a component of kidney disease. Mice lacking albumin were healthy and indistinguishable from control littermates, although they developed hypertriglyceridemia. Dyslipidemia was observed in Alb(+/-) mice, which displayed half the normal plasma albumin concentration. Alb mutant mice were bred to collagen-alpha(3)(IV) knockout (Col4a3(-/-)) mice, which are a model for human Alport syndrome. Lack of circulating and filtered albumin in Col4a3(-/-); Alb(-/-) mice resulted in dramatically improved kidney disease outcomes, as these mice lived 64% longer than did Col4a3(-/-); Alb(+/+) and Col4a3(-/-); Alb(+/-) mice, despite similar blood pressures and serum triglyceride levels. Further investigations showed that the absence of albumin correlated with reduced transforming growth factor-beta(1) signaling as well as reduced tubulointerstitial, glomerular, and podocyte pathology. We conclude that filtered albumin is injurious to kidney cells in Alport syndrome and perhaps in other proteinuric kidney diseases, including diabetic nephropathy.