Glomerular filtration and podocyte tensional homeostasis: importance of the minor type IV collagen network.

Abstract

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 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.