Expression of a system L neutral amino acid transporter at the blood–brain barrier

Matsuo, Hirotaka; Tsukada, Shingo; Nakata, Takashi; Chairoungdua, Arthit; Kim, Do Kyung; Ho, Seok; Inatomi, Jun; Yorifuji, Hiroshi; Fukuda, Jun; Endou, Hitoshi; Kanai, Yoshikatsu

doi:10.1097/00001756-200011090-00021

Cited by 130 publications

(94 citation statements)

References 10 publications

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“…The immunostaining intensity of LAT1, however, was increased in the kidney sections of CGN rats on day 7, although its subcellular granular pattern in the cytoplasm remained unchanged (Figure 6b, day 7, inset). Positive staining of LAT1 in the capillary endothelial cells of bloodbrain barrier 30,31 further confirmed the specificity of the anti-LAT1 antibody (Figure 6b, control, inset). A previous study showed a predominant expression of LAT2 at the basolateral membrane of proximal tubules.…”

Section: Expression Of Lats In Normal and Crescentic Glomerulisupporting

confidence: 63%

“…25,26 So far, four LATs (LAT1-LAT4) have been identified at the molecular level. LAT1 27 has been found in many malignant cells; 28,29 however, its clear expression in normal tissues has been only reported in the vascular endothelial cells forming the blood-brain barrier 30,31 and syncytiotrophoblastic cells of the placenta. 32 Expression of LAT2 has been shown in the epithelium of kidney proximal tubules and the digestive tract.…”

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confidence: 99%

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Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

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Section: Expression Of Lats In Normal and Crescentic Glomerulisupporting

confidence: 63%

mentioning

confidence: 99%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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“…LAT1 has been shown to be highly expressed in a wide range of cancer cells (20,21), but the role of LAT1 in normal cells has not been determined because its expression in normal tissues is extremely low (20,22,23). In this study, we demonstrated that full activation of primary human T cells by TCR stimulation and costimulation triggers dramatic induction of LAT1 expression that is mediated by NF-kB and AP-1.…”

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confidence: 67%

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Hayashi

Jutabha

Endou³

et al. 2013

The Journal of Immunology

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115

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Activation of T cells accompanies remarkable enhancement of metabolism. Sufficient and continuous nutrient supply is therefore important to support immune reaction in T cells. However, the mechanism of the promotion of nutrient incorporation in activated T cells has not been elucidated. In this study, we show that L-type amino acid transporter 1 (LAT1) is a major transporter for essential amino acids into activated human T cells. CD3/CD28 stimulation in primary human T cells triggered dramatic induction of LAT1 expression mediated by NF-κB and AP-1. Functional disturbance of LAT1 by a specific inhibitor and by small interfering RNA in human T cells suppressed essential amino acid uptake and induced a stress response mediated by DNA damage–inducible transcript 3 to attenuate cytokine production via inhibition of NF-κB and NFAT activities. These results uncover the previously unknown mechanism by which T cells accelerate essential amino acid uptake upon activation and adapt to essential amino acid starvation. Our results also raise the possibility for application of an LAT1 inhibitor as a new drug for therapy of disease caused by exaggerated immune response.

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“…For negative control, incubation step with the primary antibody was omitted. The specificity of immunoreactions using the anti-LAT1 antibody was established in previous studies (Matsuo et al, 2000;Nawashiro et al, 2006). LAT1 expression was considered positive only if distinct membrane staining was present.…”

Section: Patientsmentioning

confidence: 99%

Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I–III nonsmall cell lung cancer

et al. 2008

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The clinical significance of L-type amino acid transporter 1 (LAT1) expression remains unclear, whereas many experimental studies have demonstrated that LAT1 is associated with the proliferation of cancer cells. The purpose of this study was to evaluate the prognostic value of LAT1 in patients with nonsmall cell lung cancer (NSCLC). A total of 321 consecutive patients with completely resected pathologic stage I -III NSCLC were retrospectively reviewed. Expression of LAT1 and proliferative activity, as determined by the Ki-67 labelling index, was also evaluated immunohistochemically and correlated with the prognosis of patients who underwent complete resection of the tumour. Expression of LAT1 was positive in 163 patients (51%) (29% of adenocaricnoma (58 of 200 patients), 91% of squamous cell carcinoma (91 of 100 patients), and 67% of large cell carcinoma (14 of 21 patients)). The 5-year survival rate of LAT1-positive patients (51.8%) was significantly worse than that of LAT1-negative patients (87.8%; Po0.001). L-type amino acid transporter 1 expression was significantly associated with lymph node metastasis and disease stage. Multivariate analysis confirmed that positive expression of LAT1 was an independent factor for predicting a poor prognosis. There was a significant correlation between LAT1 expression and Ki-67 labelling index. LAT1 expression is a promising pathological factor to predict the prognosis in patients with resectable stage I -III NSCLC.

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Expression of a system L neutral amino acid transporter at the blood–brain barrier

Cited by 130 publications

References 10 publications

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I–III nonsmall cell lung cancer

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