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Modeling proximal tubule cell homeostasis: tracking changes in luminal flow. (English) Zbl 1171.92018
Summary: During normal kidney function, there are routinely wide swings in proximal tubule fluid flow and proportional changes in \(\text{Na}^{+}\) reabsorption across tubule epithelial cells. This “glomerulotubular balance” occurs in the absence of any substantial change in cell volume, and is thus a challenge to coordinate luminal membrane solute entries with peritubular membrane solute exits. In this work, linear optimal control theory is applied to generate a configuration of regulated transporters that could achieve this result. A previously developed model of rat proximal tubule epithelium is linearized about a physiologic reference condition; the approximate linear system is recast as a dynamical system, and a Riccati equation is solved to yield the optimal linear feedback that stabilizes \(\text{Na}^{+}\) flux, cell volume, and cell pH.
The first observation is that optimal feedback control is largely consigned to three physiologic variables: cell volume, cell electrical potential, and lateral intercellular hydrostatic pressure. Parameter modulation by cell volume stabilizes cell volume; parameter modulation by electrical potential or interspace pressure act to stabilize \(\text{Na}^{+}\) flux and cell pH. This feedback control is utilized in a tracking problem, in which reabsorptive \(\text{Na}^{+}\) flux varies over a factor of two, in order to represent a substantial excursion of glomerulotubular balance. The resulting control parameters consist of two terms, an autonomous term and a feedback term, and both terms include transporters on both luminal and peritubular cell membranes.
Overall, the increase in \(\text{Na}^{+}\) flux is achieved with upregulation of luminal \(\text{Na}^{+}/\text{H}^{+}\) exchange and \(\text{Na}^{+}\)-glucose cotransport, with increased peritubular \(N\text{Na}^{+}-3\text{HCO}_{3}^{-}\) and \(\text{K}^{+}-\text{Cl}^{-}\) cotransport, and with increased \(\text{Na}^{+}, \text{K}^{+}\)-ATPase activity. The configuration of activated transporters emerges as a testable hypothesis of the molecular basis for glomerulotubular balance. It is suggested that the autonomous control component at each cell membrane could represent the cytoskeletal effects of luminal flow.

92C30 Physiology (general)
92C35 Physiological flow
93B52 Feedback control
93C95 Application models in control theory
92-08 Computational methods for problems pertaining to biology
Full Text: DOI
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