Growth arrest-specific gene 6 is involved in glomerular hypertrophy in the early stage of diabetic nephropathy.
Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.
Nagai
Kojiro
K
Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Arai
Hidenori
H
Yanagita
Motoko
M
Matsubara
Takeshi
T
Kanamori
Hiroshi
H
Nakano
Toru
T
Iehara
Noriyuki
N
Fukatsu
Atsushi
A
Kita
Toru
T
Doi
Toshio
T
D000419:Albuminuria; D000818:Animals; D015153:Blotting, Western; D003928:Diabetic Nephropathies / Q000378:metabolism*; D018450:Disease Progression; D005434:Flow Cytometry; D005919:Glomerular Filtration Rate; D006801:Humans; D006984:Hypertrophy / Q000473:pathology*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D007930:Leucine / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014859:Warfarin / Q000494:pharmacology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D007930:Leucine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014859:Warfarin; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat