Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Albuminuria
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Animals
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Axl Receptor Tyrosine Kinase
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Blotting, Western
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Diabetic Nephropathies / metabolism*
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Disease Progression
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Flow Cytometry
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Glomerular Filtration Rate
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Humans
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Hypertrophy / pathology*
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Immunohistochemistry
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Intercellular Signaling Peptides and Proteins*
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Kidney / metabolism
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Kidney Diseases / metabolism
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Kidney Diseases / pathology*
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Leucine / chemistry
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Oncogene Proteins / metabolism
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Proteins / metabolism*
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Proteins / physiology*
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Proto-Oncogene Proteins
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Rats
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Receptor Protein-Tyrosine Kinases / metabolism
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Recombinant Proteins / metabolism
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Time Factors
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta1
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Warfarin / pharmacology
Substances
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Intercellular Signaling Peptides and Proteins
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Oncogene Proteins
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Proteins
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Proto-Oncogene Proteins
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Recombinant Proteins
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Tgfb1 protein, rat
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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growth arrest-specific protein 6
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Warfarin
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Receptor Protein-Tyrosine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Leucine
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Axl Receptor Tyrosine Kinase