Axial Flow Effects in Proximal Tubule

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DESCRIPTION (provided by applicant): Glomerulotubular balance (GTB) is a critical aspect of proximal tubule transport, that maintains nearly proportional change in reabsorption of Na+, HCO3-, C1-, and water with variation in glomerular filtration (GFR). GTB acts to prevent renal solute loss following a GFR increase, and also allows preservation of adequate distal isodium delivery in times of low GFR, thus limiting compromise of distal nephron acid and potassium excretion. The mechanisms by which GFR can modulate proximal reabsorption are uncertain, although it is well established that variation in axial flow of tubular fluid can, by itself, induce proportional changes in Na+ transport. We hypothesize that brush border microvilli are the sensors for transducing the signal of increased flow rate, and that the downstream ion exchanger on the apical membrane NHE3 is the key effector for increasing the reabsorption of Na+, HCO3- and fluid. A recent mathematical model of fluid flow within the proximal tubule brush border supports the idea that the microvilli configuration is ideally suited for them to serve as the mechanosensors of proximal tubule fluid flow. In the work proposed, both in vivo and in vitro microperfusion experiments will be conducted with the following three aims: 1) To test whether brush border microvilli act as mechanotransducers that sense axial flow in rat and mouse proximal tubules; 2) To examine whether the increment of proximal tubule transport attributed to enhanced flow rate is due to increasing transcellular transport via NHE3, rather than by changing the physical factors that alter the epithelial permeability and increase paracellular transport; and 3) utilize both knockout animals and inhibitors to define key cytosolic mediators of flow-dependent transport. The unique features of our proposed collaboration are: (1) the comparison of flow-dependent proximal tubule transport, both in vivo and in vitro microperfusion in mice and in knockout animals; (2) the representation of reabsorptive fluxes as a function of hydrodynamic forces and torques on microvilli; (3) the development of a model to explain the non-linear relationship between flow and reabsorption that takes account of changing tubule and microvilli geometry and (4) the assessment of transport and permeability data within a mathematical model of proximal tubule transport. These studies will provide new information on mechanisms of GTB and aspects of renal fluid and HCO3- transport in physiological and pathophysiological conditions.