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.

哺乳动物肾脏不断过滤大量液体，血浆中白蛋白和其他大分子几乎完全保留。三层肾脏滤过屏障的破坏导致小肾脏毛细血管壁上的白蛋白流失到尿液（白蛋白尿）中，并且是导致慢性肾脏疾病的主要原因。然而，对于肾脏滤器的确切工作原理以及为什么其渗透性在肾脏疾病中发生改变的原因知之甚少。在这里，我们显示肾过滤器的渗透性是通过压缩毛细血管壁来调节的。我们在与影响肾脏滤过屏障的人类遗传疾病等效的小鼠模型中，在蛋白尿发作之前和之后收集形态计量学数据。将定量分析与数学建模相结合，我们证明肾小球滤过屏障的形态改变导致降低的压缩力，抵消了滤压，从而导致毛细血管扩张，最终导致白蛋白尿。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有缺陷的肾脏滤过的分子理解。