Organic anion transporter OAT1 is involved in renal handling of citrulline

Abstract

Because citrulline plasma concentration is elevated in kidney failure, citrulline could be a biomarker of renal insufficiency, although the mechanism regulating its disposition in the kidney has not been clarified. In rat kidney slices, citrulline uptake was apparently Na+ dependent, saturable with Km 556 μM, and significantly inhibited by anionic (PAH) and cationic (TEA) compounds, but not by probenecid at 1 mM. Preincubation of kidney slices with glutarate increased citrulline uptake, while such an increase was not observed after preincubation of the slices in Na+-free buffer. This result suggested that a sodium-dependent dicarboxylate cotransporter is involved in citrulline uptake by rat kidney slices. In studies using transporter-overexpressing cells, human organic anion transporter 1 (OAT1) and rat Oat1 exhibited citrulline transport activity with Km values of 238 and 373 μM, respectively, while other OATs and organic cation transporters (OCTs) did not transport citrulline. Based on the relative activity factor method, the contribution of rat Oat1 to the overall uptake of citrulline in rat kidney slices was ∼70%. Moreover, the interaction among citrulline, PAH, and probenecid uptakes via rat Oat1 suggested that there are multiple functional sites on Oat1 and that the citrulline site may be distinct from the PAH and probenecid site. Thus OAT1/Oat1 appears to be one of the major contributors to renal basolateral uptake of citrulline, and impaired activities of these transporters may contribute substantially to the increase in plasma citrulline in renal failure. Accordingly, citrulline may be useful for diagnosis of kidney function as is creatinine.

In vivo renal arginine release is impaired throughout development of chronic kidney disease

“…In the kidney, Mitsuoka et al (19) identified B(0)AT1 and b(0,ϩ)AT, sodiumindependent and -dependent transporters of citrulline on the apical membrane of cultured rat renal proximal tubular cells. On the basolateral side of the proximal tubules, sodiumindependent transporters are present and OAT1 is the primary basolateral transporter (22). Giusto et al (11) demonstrated a reduction in basolateral OAT1 following renal ischemia-reperfusion injury in rats.…”

Extracellular ATP Hydrolysis Inhibits Synaptic Transmission by Increasing pH Buffering in the Synaptic Cleft

“…The only other proteins known to be inhibited by probenecid are OATs [67]. OAT1 is expressed in the brain [68], but retinal expression in fish has not been assessed.…”

Prolonged Hypoxia Augments L-Citrulline Transport By System A In The Newborn Piglet Pulmonary Circulation

“…For example, studies with rat kidney slices found that basolateral L-citrulline uptake was largely due to the Na + -independent organic anion transporter, OAT1. 34 Yet, in studies with rat renal proximal tubular epithelial cells and the human kidney proximal tubular epithelial cell line, HK-2, apical uptake of L-citrulline was shown to be mediated by at least two distinct Na + -dependent transport systems and one Na + -independent transport system. 35 Likewise, studies with Caco-2 cells, a model of human intestinal epithelial cells, found that apical L-citrulline uptake was mediated both by Na + -dependent (via System B (0,+) ) and Na + -independent (via Systems Figure 5 Citrulline uptake in PAECs cultured under normoxic and hypoxic conditions for 24, 48, or 72 h: (A) total uptake; (B) System A-mediated uptake (determined by the use of amino acid competitors to select for System A: glutamine, histidine, threonine, and leucine, amino acids preferentially transported by Systems N, ASC, and L, respectively); (C) System N-mediated uptake (determined by the use of amino acid competitors to select for System N: 2-methylaminoisobutyric acid, leucine, and threonine, amino acids preferentially transported by Systems A, L, or ASC, respectively).…”