Simulations of increased glomerular capillary wall strain in the 5/6-nephrectomized rat

Chronic glomerular hypertension is associated with glomerular injury and sclerosis; however, the mechanism by which increases in pressure damage glomerular podocytes remains unclear. We tested the hypothesis that increases in glomerular pressure may deleteriously affect podocyte structural integrity by increasing the strain of the glomerular capillary walls, and that glomerular capillary wall strain may play a significant role in the perpetuation of glomerular injury in disease states that are associated with glomerular hypertension.

We developed an anatomically accurate mathematical model of a compliant, filtering rat glomerulus to quantify the strain of the glomerular capillary walls in a remnant glomerulus of the 5/6-nephrectomized rat model of chronic kidney disease. In terms of estimating the mechanical stresses and strains in the glomerular capillaries, this mathematical model is a substantial improvement over previous models which do not consider pressure-induced alterations in glomerular capillary diameters in distributing plasma and erythrocytes throughout the network.

Using previously reported data from experiments measuring the change of glomerular volume as a function of perfusion pressure, we estimated the Young's modulus of the glomerular capillary walls in both control and 5/6-nephrectomized conditions. We found that in 5/6-nephrectomized conditions, the Young's modulus increased to 8.6 MPa from 7.8 MPa in control conditions, but the compliance of the capillaries increased in 5/6-nephrectomized conditions due to a 23.3% increase in the baseline glomerular capillary diameters. We found that glomerular capillary wall strain was increased approximately threefold in 5/6-nephrectomized conditions over control, which may deleteriously affect both mesangial cells and podocytes. The magnitudes of strain in model simulations of 5/6-nephrectomized conditions were consistent with magnitudes of strain that elicit podocyte hypertrophy and actin cytoskeleton reorganization in vitro.

Our findings indicate that glomerular capillary wall strain may deleteriously affect podocytes directly, as well as act in concert with other mechanical changes and environmental factors inherent to the in vivo setting to potentiate glomerular injury in severe renoprival conditions.