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 transporter-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.

Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions

“…These agents have natriuretic effects and block Na/H + exchanger NHE3, decreasing blood pressure, and modifying hemodynamics and endothelial function. In experimental models, these effects on the NHE3 exchanger modify intracellular and mitochondrial calcium concentrations, which may have significant physiological implications [ 101 ].…”

Efficacy of different urinary uric acid indicators in patients with chronic kidney disease

“…In addition, it has been proved that multiple uric acid transporters are expressed at the apical and basolateral membranes of proximal tubule which coupled with numerous solutes to regulate uric acid influx and efflux. Due to the abnormal activation of renin-angiotensin-aldosterone system (RAAS) and parathyroid hormone (PTH) of CKD, ANG II and PTH stimulate the coupled entry of Na + and lactate which in turn increase urate/lactate exchange across urate transporter 1 (URAT1) causing reduced uric acid excretion [9]. Therefore, the reduced glomerular filtration and deregulated RAAS and PTH in maintaining the balance of uric acid in CKD must not be ignored.…”

The Combined Use of Fractional Urate and Potassium Excretion in the Diagnosis of Diuretic-Induced Hyponatremia

“…Serum uric acid (sUA) and its fraction excretion are valuable markers to identify the volemic status in acute patients. The renal handling of uric acid is exclusively in the proximal tubule, preserved by interferences induced by the most used diuretics [ 20 ]. Moreover, fractional excretions on a urine spot sample represent an accurate parameter avoiding 24 h urine collection [ 21 ].…”