Essential role of Gas6 for glomerular injury in nephrotoxic nephritis.
Growth-arrest specific gene 6 (Gas6) is a vitamin K-dependent growth factor for mesangial and epithelial cells. To investigate whether Gas6 is essential for progressive glomerular injury, we constructed Gas6(-/-) mice and examined the role of Gas6 in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis. We found less mortality and proteinuria in Gas6(-/-) mice than in wild-type mice following injection of nephrotoxic serum. Glomerular cell proliferation, glomerular sclerosis, crescent formation, and deposition of fibrin/fibrinogen in glomeruli were also reduced in Gas6(-/-) mice. Furthermore, administering Gas6(-/-) mice recombinant wild-type Gas6, but not Gas6 lacking a previously characterized N-terminal gamma-carboxyl group, induced massive proteinuria, glomerular cell proliferation, and glomerulosclerosis, comparable to responses seen in wild-type mice. These data indicate that Gas6 induces glomerular cell proliferation in NTN and suggest that this factor contributes to glomerular injury and the progression of chronic nephritis.
Yanagita
Motoko
M
Department of Geriatric Medicine, Kyoto University, Kyoto, Japan.
Ishimoto
Yoshikazu
Y
Arai
Hidenori
H
Nagai
Kojiro
K
Ito
Tsuyoshi
T
Nakano
Toru
T
Salant
David J
DJ
Fukatsu
Atsushi
A
Doi
Toshio
T
Kita
Toru
T
D000818:Animals; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005921:Glomerulonephritis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007074:Immunoglobulin G / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D012756:Sheep; D015534:Trans-Activators / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
D004268:DNA-Binding Proteins; D005337:Fibrin; D005340:Fibrinogen; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000099255:Growth Arrest-Specific Protein 6; C494087:Stat3 protein, mouse