Transport characteristics of <scp>L</scp>‐citrulline in renal apical membrane of proximal tubular cells

Mitsuoka, Keisuke; Shirasaka, Yoshiyuki; Fukushi, Akimasa; Sato, Masanobu; Nakamura, Toshimichi; Nakanishi, Takeo; Tamai, Ikumi

doi:10.1002/bdd.653

Cited by 21 publications

(14 citation statements)

References 40 publications

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“…Transplacental transport of citrulline is not well characterized. In the rat small intestine and the apical membrane of renal proximal tubular cells, citrulline transport appears to occur via Na + -dependent systems [40, 41]. IUGR is associated with elevated levels of maternal arginine [42], but intracellular arginine and citrulline are reduced in human umbilical vein cells (HUVECs) [39].…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Placental Transport of Amino Acids Precedes the Development of Intrauterine Growth Restriction in Maternal Nutrient Restricted Baboons

Pantham

Rosario

Weintraub

et al. 2016

Biology of Reproduction

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Intrauterine growth restriction (IUGR) is an important risk factor for perinatal complications and adult disease. IUGR is associated with down-regulation of placental amino acid transporter expression and activity at birth. It is unknown whether these changes are a cause or a consequence of human IUGR. We hypothesized that placental amino acid transport capacity is reduced prior to onset of reduced fetal growth in baboons with maternal nutrient restriction (MNR). Pregnant baboons were fed either a control (n ¼ 8) or MNR diet (70% of control diet, n ¼ 9) from Gestational Day 30. At Gestational Day 120 (0.65 of gestation), fetuses and placentas were collected. Microvillous (MVM) and basal (BM) plasma membrane vesicles were isolated. System A and system L transport activity was determined in MVM, and leucine transporter activity was assessed in BM using radiolabeled substrates. MVM amino acid transporter isoform expression (SNAT1, SNAT2, and SNAT4 and LAT1 and LAT2) was measured using Western blots. LAT1 and LAT2 expression were also determined in BM. Maternal and fetal plasma amino acids concentrations were determined using mass spectrometry. Fetal and placental weights were unaffected by MNR. MVM system A activity was decreased by 37% in MNR baboon placentas (P ¼ 0.03); however MVM system A amino acid transporter protein expression was unchanged. MVM system L activity and BM leucine transporter activity were not altered by MNR. Fetal plasma concentrations of essential amino acids isoleucine and leucine were reduced, while citrulline increased (P , 0.05) in MNR fetuses compared to controls. In this primate model of IUGR, placental MVM system A amino acid transporter activity is decreased prior to the onset of reduction in the fetal growth trajectory. The reduction in plasma leucine and isoleucine in MNR fetuses may be caused by reduced activity of MVM system A, which is strongly coupled with system L essential amino acid uptake. Our findings indicate that reduced placental amino acid transport may be a cause rather than a consequence of IUGR due to inadequate maternal nutrition.

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Section: Discussionmentioning

confidence: 99%

Down-Regulation of Placental Transport of Amino Acids Precedes the Development of Intrauterine Growth Restriction in Maternal Nutrient Restricted Baboons

Pantham

Rosario

Weintraub

et al. 2016

Biology of Reproduction

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“…There are sodium-independent transporters in the nervous system (26) and sodium-dependent transporters in rat endothelial cells (33). 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).…”

Section: Discussionmentioning

confidence: 99%

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

Chen¹,

Baylis

2010

American Journal of Physiology-Renal Physiology

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The kidney is a major site of arginine synthesis where citrulline is converted to arginine via argininosuccinate synthase (ASS) and lyase (ASL). The rate-limiting step in arginine synthesis by the normal kidney is the rate of citrulline delivery and uptake to the renal cortex. We tested whether with chronic kidney disease (CKD) renal arginine synthesis may be compromised. Using the 5/6 renal ablation/infarction (A/I) injury model, we measured renal citrulline delivery and uptake as well as arginine release at early, moderate, and severe stages of CKD vs. healthy controls. The renal plasma flow (RPF) and arterial-renal venous difference was measured at baseline and during citrulline infusion. Citrulline delivery was reduced at all stages of disease due to marked reductions in RPF and despite moderately increased plasma citrulline. Early after 5/6 A/I, the kidney demonstrated a compensatory increase in citrulline uptake while at moderate and severe injury baseline citrulline uptake fell. At all stages of CKD, renal arginine release was markedly reduced. Citrulline infusion increased plasma citrulline in all groups, resulting in increased renal delivery vs. baseline. In healthy kidneys and early injury, citrulline uptake increased with the infusion, but only in the normal kidney did arginine production increase in parallel with the increased citrulline uptake. At moderate and severe injury, there was no increase in citrulline uptake or arginine production. The fall in arginine production in 5/6 A/I was due to an early loss of ASS and ASL conversion of citrulline, which combined with a later reduction in citrulline uptake.

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“…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). All studies were performed in triplicate using PAECs from three to four different piglets.…”

Section: Figure 4 (A -D)mentioning

confidence: 99%

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

Fike

Sidoryk‐Węgrzynowicz

Aschner

et al. 2012

B63. Experimental Models in Pulmonary Hypertension I

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AimsPulmonary arterial endothelial cells (PAECs) express the enzymes needed for generation of L-arginine from intracellular L-citrulline but do not express the enzymes needed for de novo L-citrulline synthesis. Hence, L-citrulline levels in PAECs are dependent on L-citrulline transport. Once generated, L-arginine can be converted to L-citrulline and nitric oxide (NO) by the enzyme NO synthase. We sought to determine whether hypoxia, a condition aetiologically linked to pulmonary hypertension, alters the transport of L-citrulline and the expression of the sodium-coupled neutral amino acid transporters (SNATs) in PAECs from newborn piglets. Methods and resultsPAECs isolated from newborn piglets were cultured under normoxic and hypoxic conditions and used to measure SNAT1, 2, 3, and 5 protein expression and 14 C-L-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. 14 C-L-citrulline uptake was increased in hypoxic PAECs. Studies with inhibitors of System A (SNAT1/2) and System N (SNAT3/5) revealed that the increased 14 C-L-citrulline uptake was largely due to System A-mediated transport. Additional studies were performed to evaluate SNAT protein expression and L-citrulline levels in lungs of piglets with chronic hypoxia-induced pulmonary hypertension and comparable age controls. Lungs from piglets raised in chronic hypoxia exhibited greater SNAT1 expression and higher L-citrulline levels than lungs from controls. ConclusionIncreased SNAT1 expression and the concomitant enhanced ability to transport L-citrulline in PAECs could represent an important regulatory mechanism to counteract NO signalling impairments known to occur during the development of chronic hypoxia-induced pulmonary hypertension in newborns. ----------------------------------------------------------------------- KeywordsPulmonary hypertension † Sodium-coupled neutral amino acid transporters † Nitric oxide

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

Cited by 21 publications

References 40 publications

Down-Regulation of Placental Transport of Amino Acids Precedes the Development of Intrauterine Growth Restriction in Maternal Nutrient Restricted Baboons

Down-Regulation of Placental Transport of Amino Acids Precedes the Development of Intrauterine Growth Restriction in Maternal Nutrient Restricted Baboons

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

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

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