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Glomerular filtration and podocyte tensional homeostasis: importance of the minor type IV collagen network.
Biomechanics and Modeling in Mechanobiology ( IF 3.5 ) Pub Date : 2020-05-27 , DOI: 10.1007/s10237-020-01347-y
Lauren M Bersie-Larson 1 , Lazarina Gyoneva 1 , Daniel J Goodman 1 , Kevin D Dorfman 2 , Yoav Segal 3, 4 , Victor H Barocas 1
Affiliation  

The minor type IV collagen chain, which is a significant component of the glomerular basement membrane in healthy individuals, is known to assemble into large structures (supercoils) that may contribute to the mechanical stability of the collagen network and the glomerular basement membrane as a whole. The absence of the minor chain, as in Alport syndrome, leads to glomerular capillary demise and eventually to kidney failure. An important consideration in this problem is that the glomerular capillary wall must be strong enough to withstand the filtration pressure and porous enough to permit filtration at reasonable pressures. In this work, we propose a coupled feedback loop driven by filtration demand and tensional homeostasis of the podocytes forming the outer portion of the glomerular capillary wall. Briefly, the deposition of new collagen increases the stiffness of basement membrane, helping to stress shield the podocytes, but the new collagen also decreases the permeability of the basement membrane, requiring an increase in capillary transmural pressure drop to maintain filtration; the resulting increased pressure outweighs the increased glomerular basement membrane stiffness and puts a net greater stress demand on the podocytes. This idea is explored by developing a multiscale simulation of the capillary wall, in which a macroscopic (µm scale) continuum model is connected to a set of microscopic (nm scale) fiber network models representing the collagen network and the podocyte cytoskeleton. The model considers two cases: healthy remodeling, in which the presence of the minor chain allows the collagen volume fraction to be increased by thickening fibers, and Alport syndrome remodeling, in which the absence of the minor chain allows collagen volume fraction to be increased only by adding new fibers to the network. The permeability of the network is calculated based on previous models of flow through a fiber network, and it is updated for different fiber radii and volume fractions. The analysis shows that the minor chain allows a homeostatic balance to be achieved in terms of both filtration and cell tension. Absent the minor chain, there is a fundamental change in the relation between the two effects, and the system becomes unstable. This result suggests that mechanobiological or mechanoregulatory therapies may be possible for Alport syndrome and other minor chain collagen diseases of the kidney.

中文翻译:

肾小球滤过和足细胞张力稳态:次要 IV 型胶原网络的重要性。

次要 IV 型胶原蛋白链是健康个体肾小球基底膜的重要组成部分,已知组装成大结构(超螺旋),这可能有助于胶原蛋白网络和肾小球基底膜作为一个整体的机械稳定性. 小链的缺失,如 Alport 综合征,会导致肾小球毛细血管死亡并最终导致肾功能衰竭。这个问题的一个重要考虑是肾小球毛细血管壁必须足够坚固以承受过滤压力,并且足够多孔以允许在合理压力下过滤。在这项工作中,我们提出了一个耦合反馈回路,该回路由形成肾小球毛细血管壁外部的足细胞的过滤需求和张力稳态驱动。简要地,新胶原蛋白的沉积增加了基底膜的硬度,有助于对足细胞进行应力屏蔽,但新胶原蛋白也降低了基底膜的渗透性,需要增加毛细血管透壁压降以维持过滤;由此产生的压力增加超过了肾小球基底膜硬度的增加,并对足细胞施加了更大的压力需求。这个想法是通过开发毛细血管壁的多尺度模拟来探索的,其中宏观(μm 尺度)连续模型连接到一组代表胶原网络和足细胞细胞骨架的微观(nm 尺度)纤维网络模型。该模型考虑两种情况:健康重塑,其中小链的存在允许通过增厚纤维增加胶原体积分数,以及 Alport 综合征重塑,其中小链的缺失允许仅通过向网络添加新纤维来增加胶原体积分数。网络的渗透率是根据先前通过纤维网络的流动模型计算得出的,并针对不同的纤维半径和体积分数进行更新。分析表明,次链允许在过滤和细胞张力方面实现稳态平衡。如果没有小链,两种效应之间的关系就会发生根本变化,系统就会变得不稳定。
更新日期:2020-05-27
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