A molecular mechanism explaining albuminuria in kidney disease
A molecular mechanism explaining albuminuria in kidney disease
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DOI：
10.1038/s42255-020-0204-y
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发表时间：
2020-05-01
影响因子：
20.8
通讯作者：
Benzing, Thomas
中科院分区：
文献类型：
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作者：
Butt, Linus;Unnersjoe-Jess, David;Benzing, Thomas
哺乳动物的肾脏不断过滤大量的液体，几乎完全保留血浆中的白蛋白和其他大分子。三层肾滤过屏障的破坏导致白蛋白穿过小肾毛细血管壁进入尿液（白蛋白尿），并且是慢性肾脏疾病的主要原因。然而，肾脏过滤器的确切工作原理以及为什么它的渗透性在肾脏疾病中发生改变，人们还知之甚少。在这里，我们表明，肾过滤器的渗透性是通过毛细血管壁的压缩调制。我们在小鼠模型中收集了白蛋白尿发作前后的形态学数据，该模型相当于影响肾滤过屏障的人类遗传性疾病。结合定量分析与数学建模，我们表明，肾小球滤过屏障的形态学改变导致压缩力减少，抵消过滤压力，从而导致毛细血管扩张，并最终蛋白尿。我们的研究结果揭示了滤过屏障不同层的不同功能，并扩展了对慢性肾脏疾病中肾滤过缺陷的分子理解。
Mammalian kidneys constantly filter large amounts of liquid, with almost complete retention of albumin and other macromolecules in the plasma. Breakdown of the three-layered renal filtration barrier results in loss of albumin into urine (albuminuria) across the wall of small renal capillaries, and is a leading cause of chronic kidney disease. However, exactly how the renal filter works and why its permeability is altered in kidney diseases is poorly understood. Here we show that the permeability of the renal filter is modulated through compression of the capillary wall. We collect morphometric data prior to and after onset of albuminuria in a mouse model equivalent to a human genetic disease affecting the renal filtration barrier. Combining quantitative analyses with mathematical modelling, we demonstrate that morphological alterations of the glomerular filtration barrier lead to reduced compressive forces that counteract filtration pressure, thereby resulting in capillary dilatation, and ultimately albuminuria. Our results reveal distinct functions of the different layers of the filtration barrier and expand the molecular understanding of defective renal filtration in chronic kidney disease.