Glomerular Capillary Hypertrophy in the Diabetic Rat Normalizes Wall Shear Stress: A Modeling Study

Abstract

Diabetes mellitus (DM) reduces renal hemodynamic autoregulation, leading to increased glomerular pressure (ΔP) and afferent plasma flow (Qa) which is assumed to increase glomerular capillary wall shear stress (SS). However, glomerular capillaries undergo hypertrophy in DM, causing an increase in capillary diameter that would theoretically reduce capillary wall SS (Seyer‐Hansen, Kjartan. Kid. Int. 23.4 (1983): 643–646.). The actual magnitudes of SS in the glomerular capillaries have not been estimated in DM and are of significance because in response to increased SS, endothelial cells increase expression of adhesion molecules and growth factors associated with glomerulopathy.We developed a mathematical model of blood flow through an anatomically‐accurate rat glomerular capillary network to estimate the magnitudes of SS on the glomerular capillary walls in DM and control. Individual filtration rates and wall SS were calculated for each capillary segment of the network based on values of Qa, ΔP and single nephron GFR (SNGFR) obtained from micropuncture studies. To validate mechanical predictions of our model, we compared our calculated SS magnitudes to results from intravital imaging studies of blood flow in rat glomeruli (Ferrell, Nicholas, et al. Am. J. Physiology‐Renal 308.6 (2015): F588‐F593.). To calculate SS magnitudes in the rat glomerulus in control and DM, we performed simulations with parameters obtained from micropuncture studies using normal rats and rats with streptozotocin induced Type I diabetes. In this study, DM increased Qa and ΔP by 74.6% and 33.3%, respectively but reduced the filtration coefficient (Kf) such that filtration fraction (FF) was maintained (Zatz, Roberto, et al. J. clin. Inv. 77.6 (1986): 1925–1930).The model was calibrated using an algorithm previously described (Remuzzi, Andrea, et al. Am. J. Physiology‐Renal 263.3 (1992): F562‐F572). Our model's calculated mean glomerular capillary wall SS was within 10% of the mean SS predicted using intravital imaging, validating our model for use in predicting mechanical aspects of blood flow in the glomerulus. Our simulations demonstrated a wide variance in SS throughout the glomerular capillary network, consistent with previous modeling results. Using parameters from micropuncture experiments and taking into account hypertrophy of the glomerular capillaries, the model predicted mean SS values of 42.1 dynes/cm2 in control and 42.3 dynes/cm2 in DM.We have developed and validated an anatomically‐accurate mathematical model of glomerular filtration for use in predicting functional and mechanical results of varied glomerular pressure, afferent plasma flow and Kf. Using this model, we demonstrated that hypertrophy of the capillaries normalizes capillary wall SS in DM, which may be a protective mechanism limiting the increase in SS and the consequent glomerular injury.Support or Funding InformationThis work was supported by the National Institute of General Medical Sciences IDeA Program (CoBRE P30GM103337) (principal investigator: L. G. Navar) O. Richfield is a graduate student supported by NSF IGERT Grant NSF DGE‐1144646.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.