Amino acid handling in uremic rats: Citrulline, a reliable marker of renal insufficiency and proximal tubular dysfunction

Levillain, Olivier; Parvy, P; Hassler, Christine

doi:10.1016/s0026-0495(97)90002-0

Cited by 39 publications

(38 citation statements)

References 18 publications

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“…However, since kidney function is maintained not only by the glomerulus but also by the PTC, a change in PTC activity, such as secretion, reabsorption, or metabolism, might be a good biomarker for a better diagnosis of kidney function. We hypothesized that citrulline, a metabolic intermediate of the urea cycle synthesized mainly in the intestine and liver, would be a good indicator of renal function, based on the previous observation of a significant change in citrulline disposition in renal failure (3,(11)(12)(13)32). Since the mechanisms of renal secretory and reabsorptive transport of citrulline are unknown, in the present study we examined the involvement of transporters in citrulline disposition in the kidney, focusing on the basolateral uptake transport process, which may be important for the increase in the plasma concentration of citrulline in renal failure.…”

Section: Discussionmentioning

confidence: 99%

“…This observation indicates that metabolic activity is not affected in kidney dysfunction, so it was considered that the change in the disposition of citrulline is largely a result of altered renal handling, including proximal tubular cell (PTC) and glomerular function. However, it was reported that the renal clearance of citrulline was less than GFR, and citrulline was reabsorbed by Ͼ90% in PTCs (13). These data suggest that citrulline could be one reliable marker for PTC function.…”

mentioning

confidence: 86%

“…Accordingly, the level of citrulline circulating in plasma is remarkably elevated in animals and humans with chronic renal failure (3,11,12,32). Moreover, the time-dependent changes in citrulline urinary and serum level in rats with 5 ⁄6 nephrectomy was found to be correlated with the degree of renal insufficiency without any change in creatininemia (13). Therefore, it is thought that citrulline could be used as a marker of renal insufficiency and uremic status, although the mechanism of its renal disposition has not yet been clarified.…”

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confidence: 99%

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Organic anion transporter OAT1 is involved in renal handling of citrulline

Nakakariya

Shima²,

Shirasaka³

et al. 2009

American Journal of Physiology-Renal Physiology

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 86%

mentioning

confidence: 99%

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Organic anion transporter OAT1 is involved in renal handling of citrulline

Nakakariya

Shima²,

Shirasaka³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…Subsequently the kidney is the major consumer of circulating citrulline extracting about 35% of arterial citrulline in each pass [80,86] . The relevance of this pathway is demonstrated quantitatively by the increase of the plasma citrulline level observed in patients with renal failure [127] .…”

Section: Metabolic Fate Of Citrulline Released Into the Portal Veinmentioning

confidence: 99%

“…This was further demonstrated by clinical data on small bowel transplantation [70][71][72][73][74][75]152] . In addition to a variation in citrulline synthesis, alterations in citrulline utilization will have an influence on the plasma citrulline concentration [80,119,127] . Plasma citrulline a surrogate endpoint for enterocyte mass Effectively, citrulline can be regarded as an endproduct of glutamine and/or proline metabolism of intestinal enterocytes [80,98,104,110,122] .…”

Section: Determinants Of Intestinal Citrulline Synthesis and Plasma Cmentioning

confidence: 99%

Biomarkers for radiation-induced small bowel epithelial damage: An emerging role for plasma Citrulline

Lutgens¹,

Lambin²

2007

WJG

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Reduction of cancer treatment-induced mucosal injury has been recognized as an important target for improving the therapeutic ratio as well as reducing the economic burden associated with these treatment related sequellae. Clinical studies addressing this issue are hampered by the fact that specific objective parameters, which enable monitoring of damage in routine clinical practice, are lacking. This review summarizes pros and cons of currently available endpoints for intestinal injury. The metabolic background and characteristics of plasma citrulline, a recently investigated biomarker specifically for small intestinal injury, are discussed in more detail.

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Transport characteristics of L‐citrulline in renal apical membrane of proximal tubular cells

Mitsuoka

Shirasaka

Fukushi

et al. 2009

Biopharm & Drug Disp

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L-Citrulline has diagnostic potential for renal function, because its plasma concentration increases with the progression of renal failure. Although L-citrulline extracted by glomerular filtration in kidney is mostly reabsorbed, the mechanism involved is not clearly understood. The present study was designed to characterize L-citrulline transport across the apical membranes of renal epithelial tubular cells, using primary-cultured rat renal proximal tubular cells, as well as the human kidney proximal tubular cell line HK-2. L-Citrulline was transported in a Na(+)-dependent manner from the apical side of both cell types cultured on permeable supports with a microporous membrane. Kinetic analysis indicated that the transport involves two distinct Na(+)-dependent saturable systems and one Na(+)-independent saturable system in HK-2 cells. The uptake was competitively inhibited by neutral and cationic, but not anionic amino acids. Relatively large cationic and anionic compounds inhibited the uptake, but smaller ones did not. In HK-2 cells, mRNA expression of SLC6A19 and SLC7A9, which encode B(0)AT1 and b(0,+)AT, respectively, was detected by RT-PCR. In addition, L-citrulline transport was significantly decreased in HK-2 cells in which either SLC6A19 or SLC7A9 was silenced. Hence, these results suggest that amino acid transporters B(0)AT1 and b(0,+)AT are involved in the reabsorption of L-citrulline in the kidney, at least in part, by mediating the apical membrane transport of L-citrulline in renal tubule cells.

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Amino acid handling in uremic rats: Citrulline, a reliable marker of renal insufficiency and proximal tubular dysfunction

Cited by 39 publications

References 18 publications

Organic anion transporter OAT1 is involved in renal handling of citrulline

Organic anion transporter OAT1 is involved in renal handling of citrulline

Biomarkers for radiation-induced small bowel epithelial damage: An emerging role for plasma Citrulline

Transport characteristics of L‐citrulline in renal apical membrane of proximal tubular cells

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