Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis.
Proliferation of mesangial cells is a hallmark of glomerular disease, and understanding its regulatory mechanism is clinically important. Previously, we demonstrated that the product of growth arrest-specific gene 6 (Gas6) stimulates mesangial cell proliferation through binding to its cell-surface receptor Axl in vitro. We also showed that warfarin and the extracellular domain of Axl conjugated with Fc portion of human IgG1 (Axl-Fc) inhibit mesangial cell proliferation by interfering the Gas6/Axl pathway in vitro. In the present study, therefore, we examined in vivo roles of Gas6 and Axl in an experimental model of mesangial proliferative glomerulonephritis induced by the injection of anti-Thy1.1 antibody (Thy1 GN). In Thy1 GN, expression of Gas6 and Axl was markedly increased in glomeruli, and paralleled the progression of mesangial cell proliferation. Administration of warfarin or daily injection of Axl-Fc inhibited mesangial cell proliferation, and abolished the induction of platelet-derived growth factor-B mRNA and protein in Thy1 GN. Moreover, the anti-proliferative effect of warfarin was achieved at lower concentrations than those in routine clinical use. These findings indicate that the Gas6/Axl pathway plays a key role in mesangial cell proliferation in vivo, and could be a potentially important therapeutic target for the treatment of renal disease.
Yanagita
M
M
Department of Geriatric Medicine, Kyoto University School of Medicine, 54 Kawahara-cho, Sho-goin, Sakyo-ku, Kyoto 606-8507, Japan. motoy@kuhp.kyoto-u.ac.jp
Arai
H
H
Ishii
K
K
Nakano
T
T
Ohashi
K
K
Mizuno
K
K
Varnum
B
B
Fukatsu
A
A
Doi
T
T
Kita
T
T
D000818:Animals; D000906:Antibodies / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000166:cytology*; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000276:immunology; D014859:Warfarin / Q000008:administration & dosage / Q000494:pharmacology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D000906:Antibodies; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D018800:Thy-1 Antigens; D014859:Warfarin; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6