title: Dual involvement of growth arrest-specific gene 6 in the early phase of human IgA nephropathy.
abstract: BACKGROUND
  Gas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN).
  
  
  METHODS
  The aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes.
  
  
  RESULTS
  In 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation.
  
  
  CONCLUSIONS
  Gas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, The University of Tokushima, Tokushima, Japan. knagai@clin.med.tokushima-u.ac.jp
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyoshi
authors.forename: Takei
authors.initials: T
authors.lastname: Kake
authors.forename: Naoshi
authors.initials: N
authors.lastname: Fukushima
authors.forename: Motokazu
authors.initials: M
authors.lastname: Matsuura
authors.forename: Eriko
authors.initials: E
authors.lastname: Shibata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamada
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Hiro-Omi
authors.initials: HO
authors.lastname: Kanayama
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fukawa
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Izaki
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.forename: Naoko
authors.initials: N
authors.lastname: Abe
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Araoka
authors.forename: Taichi
authors.initials: T
authors.lastname: Murakami
authors.forename: Fumi
authors.initials: F
authors.lastname: Kishi
authors.forename: Seiji
authors.initials: S
authors.lastname: Kishi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tominaga
authors.forename: Tatsumi
authors.initials: T
authors.lastname: Moriya
authors.forename: Hideharu
authors.initials: H
authors.lastname: Abe
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005922:Glomerulonephritis, IGA / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D050527:Mesangial Cells / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000099255:Growth Arrest-Specific Protein 6