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 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.

Keywords: Biomechanics; Capillary; Growth; Kidney; Remodeling; Stability.

Figure 1.. Model Schematic.

(a) Conceptual schematic of the glomerular capillary wall, consisting of four distinct layers from the innermost endothelial layer to the outermost podocyte (epithelial) layer. (b) Finite element model geometry consisting of a quarter cylinder containing major-chain, minor-chain, and podocyte layers, each represented using our multiscale modeling scheme and underlying collagen IV networks (for GBM) or actin filament networks (for podocytes).

Figure 2.. Model of Major-Chain vs. Minor-Chain Deposition.

Since the major chain (upper row) does not supercoil significantly, volume was added to a major-chain network by increasing the number of fibers. For minor-chain networks (lower row), however, volume was added by increasing fiber radius, representing the new collagen supercoiling with fibers in the existing matrix.

Figure 3.. GBM Material Property Changes with Collagen Volume Fraction.

(a) Compliance decreases (i.e., stiffness increases) with increased collagen level in both cases, with the healthy case showing a slightly stronger effect. (b) Permeability decreases with increased collagen level in both cases, but the Alport case shows a much larger decrease.

Figure 4.. Podocyte Tension Changes with Collagen Volume Fraction.

In the Alport case, the addition of more collagen drives up the cell stress because the increased pressure required to overcome the decreased permeability has more impact on cell stress than the increased shielding due to a stiffer matrix. For the healthy case, the shielding effect is stronger than the permeability/pressure effect, so the net effect is to drive down the cell stress at higher collagen levels.

Figure 5.. Circumferential stress (σ_θθ) in the different layers of the simulated glomerular capillary wall.

(a) Baseline (φ₀ = 0.04). (b) Remodeled healthy (φ = 0.06). (c) Remodeled Alport (φ = 0.06). Colorbar is the same for all three cases. The remodeled healthy case (b) shows a slightly higher collagen stress due to the increased pressure necessary for filtration but a lower cell stress as the stiffer collagen layers protect the cells. In the Alport case (c), in contrast, the large drop in permeability (Figure 4b) leads to increased stress in both the collagen and the cell layers.

Figure 6.. Capillary Pressure - Collagen Volume Fraction Operating Curves.

(a) Healthy Case. There are two lines, one (filtration homeostasis) describing the pressure necessary to maintain the target filtration rate for a given collagen level, and the other (tensional homeostasis) describing the necessary collagen level to produce a tissue stiff enough to achieve the target cell stress at a given capillary pressure. Equilibrium is achieved where the two lines cross. (b) Alport Case. The lines have the same meaning, but now the filtration line is both higher and steeper, leading to no stable equilibrium condition.