title: Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis.
abstract: 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.
authors.affiliation: Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kurayama
authors.forename: Noriko
authors.initials: N
authors.lastname: Ito
authors.forename: Yukino
authors.initials: Y
authors.lastname: Nishibori
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fukuhara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Akimoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Higashihara
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Yoshikatstu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Yan
mesh_terms: D027182:Amino Acid Transport System y+ / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D005260:Female; D027301:Fusion Regulatory Protein 1, Light Chains / Q000502:physiology*; D005921:Glomerulonephritis / Q000209:etiology / Q000503:physiopathology*; D007150:Immunohistochemistry; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D027182:Amino Acid Transport System y+; D017931:DNA Primers; D027301:Fusion Regulatory Protein 1, Light Chains; C486582:Slc7a8 protein, rat; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases