Calcium dynamics underlying the myogenic response of the renal afferent arteriole

Abstract

The renal afferent arteriole reacts to an elevation in blood pressure with an increase in muscle tone and a decrease in luminal diameter. This effect, known as the myogenic response, is believed to stabilize glomerular filtration and to protect the glomerulus from systolic blood pressure increases, especially in hypertension. To study the mechanisms underlying the myogenic response, we developed a mathematical model of intracellular Ca(2+) signaling in an afferent arteriole smooth muscle cell. The model represents detailed transmembrane ionic transport, intracellular Ca(2+) dynamics, the kinetics of myosin light chain phosphorylation, and the mechanical behavior of the cell. It assumes that the myogenic response is initiated by pressure-induced changes in the activity of nonselective cation channels. Our model predicts spontaneous vasomotion at physiological luminal pressures and KCl- and diltiazem-induced diameter changes comparable to experimental findings. The time-periodic oscillations stem from the dynamic exchange of Ca(2+) between the cytosol and the sarcoplasmic reticulum, coupled to the stimulation of Ca(2+)-activated potassium (KCa) and chloride (ClCa) channels, and the modulation of voltage-activated L-type channels; blocking sarco/endoplasmic reticulum Ca(2+) pumps, ryanodine receptors (RyR), KCa, ClCa, or L-type channels abolishes these oscillations. Our results indicate that the profile of the myogenic response is also strongly dependent on the conductance of ClCa and L-type channels, as well as the activity of plasmalemmal Ca(2+) pumps. Furthermore, inhibition of KCa is not necessary to induce myogenic contraction. Lastly, our model suggests that the kinetic behavior of L-type channels results in myogenic kinetics that are substantially faster during constriction than during dilation, consistent with in vitro observations (Loutzenhiser R, Bidani A, Chilton L. Circ. Res. 90: 1316-1324, 2002).

A Multicellular Vascular Model of the Renal Myogenic Response

“…Vascular diameter across the model vessel greatly impacts hemodynamics [7], and we combine the myogenic mechanisms of a large number of smooth muscle cells that are the main determinants of vascular tone and wall mechanics [3]. For the myogenic mechanism of each smooth muscle cell we adopt a highly detailed model of subcellular dynamics that has been previously applied on the renal afferent arteriole myocytes [29]. Additionally, to represent accurately conducted responses that have been shown, experimentally and theoretically, to have a significant effect on overall autoregulation [17,24,27,53,54], we incorporate gap junction coupling directly among neighboring smooth muscle cells as well as among smooth muscle cells and a layer of endothelial cells.…”

“…However, theoretically a deeper understanding of the involved processes is lacking which limits our ability to investigate in silico realistic scenarios under health or disease conditions. For example, although several models accurately represent the myogenic response at the vascular or supravascular levels [2,7,11,[19][20][21][22][23][24][25][26][27][28], and few even at the cellular level [6,29,30], none of the existing models attempt to model the myogenic response across multiple scales.…”

“…Our previous modeling study [29] considered only a single afferent arteriole smooth muscle cell and investigated the myogenic response initiated by pressure changes. In [7], we considered a model exhibiting the myogenic response and consisting of an afferent arteriole segment, glomerular filtration, and a short loop of Henle.…”

“…In [7], we considered a model exhibiting the myogenic response and consisting of an afferent arteriole segment, glomerular filtration, and a short loop of Henle. The smooth muscle cell in this study is less realistic than the model in [29] since it includes a small number of components, such as membrane potential and calcium concentration. In [30], we extended the model in [29] to a segment of multiple smooth muscle cells connected through gap junctions; one limitation of this model is that the numerical implementation (fractional splitting) did not allow us to consider a realistic cell size.…”

“…Another goal is to formulate a realistic model entailing a feasible computational cost that may be further extended to larger scales. To that end, we expand on our existing, highly detailed mathematical model of Ca 2+ signaling within an individual afferent arteriole smooth muscle cell [29] that represents the transmembrane transport of major cytosolic ions, intracellular Ca 2+ dynamics, the kinetics of myosin light chain phosphorylation, and the mechanical behavior of the entire cell and local vascular wall. We extend this model to a multi-cell vascular model of the afferent arteriole and couple it with a representation of hemodynamics, i.e., blood flow and pressure, and intercellular conduction that also incorporates a layer of endothelial cells.…”