Quantifying Mechanical Stress in the Remaining Glomeruli in 5/6‐Nephrectomy

Abstract

The purpose of the present study was to estimate the increases in mechanical stress in remnant rat glomeruli after 5/6‐nephrectomy. In cases of reduction of renal mass there is increased glomerular blood flow and pressure in the remnant glomeruli. These altered hemodynamic conditions are believed to result in increased shear stress on and strain of the glomerular capillary walls, however the actual magnitudes of these stresses have not been estimated. These magnitudes are of importance given the inflammatory reaction of endothelial cells and podocytes to excess shear stress and strain, respectively. In response to increased shear stress, vascular endothelial cells increase production of TGF‐β1, a pro‐fibrotic factor implicated in numerous kidney diseases. Sustained increased fluid flow shear stress also raises endothelial cell production of ICAM‐1 which contributes to the initiation of the inflammatory process. TGF‐β and cyclic stretch cause podocyte detachment from the glomerular capillary and hypertrophy of the remaining podocytes.We developed an anatomically accurate mathematical model of the rat glomerulus which calculates blood flow and filtration on each segment of a rat glomerular capillary network. The model takes into account conservation of plasma protein mass and hematocrit distribution, allowing for simulation of the non‐Newtonian aspects of blood flow in calculating shear stresses on the vessel walls. Hemodynamic parameters were taken from glomerular micropuncture studies of 5/6‐nephrectomized animals to simulate these disease states (Kasiske, Bertram L., et al. Circulation Research 62.2 (1988): 367–374). Our 5/6‐nephrectomy results were validated by comparison to a study which utilized intravital imaging to estimate glomerular capillary wall shear stress in vivo (Ferrell, Nicholas, et al. Amer. J. of Physiology‐Renal 308.6 (2015): F588–F593).The model demonstrates that most of the filtration occurs near the afferent arteriole. Hoop stress, an index of strain, is highest in the large diameter vessels branching off the afferent arteriole, whereas shear stress is highest in the vessels closer to the efferent arteriole, primarily due to a concentration of hematocrit in those vessels from fluid volume loss via filtration. Despite an increase in capillary diameter via a hypertrophic response in the 5/6‐nephrectomy model, the shear stress was significantly elevated. Hoop stress was elevated due to the increased pressure in 5/6‐nephrectomy.Through the of use of an anatomically‐accurate mathematical model of the rat glomerulus we calculated significant increases of hoop and shear stresses in 5/6‐nephrectomy. These results indicate that increased mechanical stress may play a significant role in the cause and/or progression of remnant glomerular injury in cases of reduced renal mass.Support or Funding InformationThis work was supported by fellowship grant NIH F31 DK121445 and the NIGMS IDeA Program (CoBRE P30GM103337). Owen Richfield is a graduate student in the Tulane University Bioinnovation PhD program supported by grants NSF IGERT DGE‐1144646 and NIH T32 EB027632.