A Novel Model of Renal Autoregulation Demonstrates Dynamic Modulatory Interactions between TGF and Myogenic Mechanisms

Abstract

The afferent arteriole regulates glomerular pressure and flow by altering its diameter in response to changes in afferent arteriole wall tension and glomerular filtration via the myogenic and tubuloglomerular feedback (TGF) mechanisms, respectively. Previous studies have indicated that TGF modulates myogenic mechanism sensitivity (Walker III, Matthew, et al. Amer. J. of Physiology-Renal 279.5 (2000): F858-F865), however the degree to which these two mechanisms interact in controlling afferent arteriole smooth muscle cell (SMC) tone remains unclear. We hypothesized that TGF signals modulate the magnitude of the myogenic response to changes in wall tension such that the TGF and myogenic mechanisms act synergistically to control afferent arteriole SMC tone. Accordingly, we developed a mathematical model of renal autoregulation that would allow for testing of differing models of convergence of the TGF and myogenic signals. We considered a “separated” model, in which the TGF and myogenic signals acted additively and independently to influence SMC tone; and an “integrated” model, in which TGF signals modulated the myogenic mechanism sensitivity in influencing SMC tone. Afferent arteriole SMC tone was translated to afferent arteriole wall tension which was used to change the diameter over time. We parameterized the afferent arteriole model according to data previously obtained using the juxtamedullary nephron preparation (Takenaka, Tsuneo, et al. Amer. J. of Physiology-Renal Physiology 267.5 (1994): F879-F887). We combined our afferent arteriole model with a model of glomerular filtration previously developed by us and a model of solute concentration dynamics on the length of the thick ascending limb of the Loop of Henle to simulate autoregulatory responses to a rapid change in perfusion pressure. By nature of the time lag of the tubule model in updating macula densa solute concentration in response to a change in SNGFR, the TGF response was delayed whereas the myogenic response was assumed to be instantaneous. We subjected each model to a step increase in perfusion pressure and compared the models’ responses to that of a model of furosemide administration which lacked TGF signals in calculating SMC tone. We found that the integrated model reached a lower minimum diameter in a shorter time duration after the pressure increase. The slope of the change in diameter immediately after the pressure increase was largest for the integrated model at 0.16 mm/s, while the separated model at 0.11 mm/s did not compete with the model lacking TGF at 0.13 mm/s. These results corroborate previous experimental findings that the speed of the myogenic constrictive response is increased with increasing signals from the macula densa, and that the myogenic mechanism is blunted in the absence of TGF input. Experiments with our novel mathematical model of renal autoregulation support the concept that the myogenic and TGF mechanisms act synergistically to control SMC tone and support the concept that the TGF mechanism modulates the sensitivity of the myogenic response.