A model of uric acid transport in the rat proximal tubule

Abstract

The objective of the present study was to theoretically investigate the mechanisms underlying uric acid transport in the proximal tubule (PT) of rat kidneys, and their modulation by factors, including Na-, parathyroid hormone, ANG II, and Na--glucose cotransporter-2 inhibitors. To that end, we incorporated the transport of uric acid and its conjugate anion urate in our mathematical model of water and solute transport in the rat PT. The model accounts for parallel urate reabsorption and secretion pathways on apical and basolateral membranes and their coupling to lactate and α-ketoglutarate transport. Model results agree with experimental findings at the segment level. Net reabsorption of urate by the rat PT is predicted to be ~70% of the filtered load, with a rate of urate removal from the lumen that is 50% higher than the rate of urate secretion. The model suggests that apical URAT1 deletion significantly reduces net urate reabsorption across the PT, whereas ATP-binding cassette subfamily G member 2 dysfunction affects it only slightly. Inactivation of basolateral glucose trans-porter-9 raises fractional urate excretion above 100%, as observed in patients with renal familial hypouricemia. Furthermore, our results suggest that reducing Na- reabsorption across Na-/H- exchangers or Na--glucose cotransporters augments net urate reabsorption. The model predicts that parathyroid hormone reduces urate excretion, whereas ANG II increases it. In conclusion, we have developed the first model of uric acid transport in the rat PT; this model provides a framework to gain greater insight into the numerous solutes and coupling mechanisms that affect the renal handing of uric acid.