Cargando…
Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells
AIM/HYPOTHESIS: Low-density lipoprotein (LDL) is subjected to glycoxidation in diabetes, and a novel signalling mechanism by which glycoxidised LDL functions in glomerular mesangial cells remains to be ascertained. METHODS: We performed gene expression analysis in mouse glomerular mesangial cells tr...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511478/ https://www.ncbi.nlm.nih.gov/pubmed/23226259 http://dx.doi.org/10.1371/journal.pone.0050297 |
_version_ | 1782251618064924672 |
---|---|
author | Kim, Young Sook Jung, Dong Ho Sohn, Eunjin Kim, Junghyun Kim, Jin Sook |
author_facet | Kim, Young Sook Jung, Dong Ho Sohn, Eunjin Kim, Junghyun Kim, Jin Sook |
author_sort | Kim, Young Sook |
collection | PubMed |
description | AIM/HYPOTHESIS: Low-density lipoprotein (LDL) is subjected to glycoxidation in diabetes, and a novel signalling mechanism by which glycoxidised LDL functions in glomerular mesangial cells remains to be ascertained. METHODS: We performed gene expression analysis in mouse glomerular mesangial cells treated with LDL modified by glycation and oxidation (GO-LDL, 100 µg/ml) for 48 h by using DNA microarray analysis and quantitative real-time PCR. We examined the GO-LDL-specific changes in gene and protein expression in mesangial cells and glomeruli of type 2 diabetic Zucker diabetic fatty (ZDF) rats. RESULTS: By microarray profiling, we noted that GO-LDL treatment increased Axl receptor tyrosine kinase (Axl) mRNA expression (∼2.5-fold, p<0.05) compared with normal LDL (N-LDL) treatment in mesangial cells. Treatment with GO-LDL also increased the protein levels of Axl and its ligand Gas6 as measured by Western blotting. These increases were inhibited by neutralising Axl receptor-specific antibody. Silencing Gas6 by siRNA inhibited GO-LDL-induced Axl expression in mesangial cells. Axl and Gas6 protein were also increased in cells cultured in high glucose (30 mM) or methylglyoxal (200 µM). Gas6 treatment increased the expression and secretion of TGF-β1 protein, a key regulator of extracellular matrix expression in the glomeruli of diabetic kidneys. Immunohistochemical analyses of glomeruli from 20-week-old ZDF rats exhibited increased Axl protein expression. Rottlerin, a selective PKC-δ inhibitor, completely blocked Gas6-induced TGF-β1 expression. CONCLUSIONS/INTERPRETATION: These data suggest that LDL modified by glycoxidation may mediate Axl/Gas6 pathway activation, and this mechanism may play a significant role in the pathogenesis of diabetic nephropathy. |
format | Online Article Text |
id | pubmed-3511478 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35114782012-12-05 Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells Kim, Young Sook Jung, Dong Ho Sohn, Eunjin Kim, Junghyun Kim, Jin Sook PLoS One Research Article AIM/HYPOTHESIS: Low-density lipoprotein (LDL) is subjected to glycoxidation in diabetes, and a novel signalling mechanism by which glycoxidised LDL functions in glomerular mesangial cells remains to be ascertained. METHODS: We performed gene expression analysis in mouse glomerular mesangial cells treated with LDL modified by glycation and oxidation (GO-LDL, 100 µg/ml) for 48 h by using DNA microarray analysis and quantitative real-time PCR. We examined the GO-LDL-specific changes in gene and protein expression in mesangial cells and glomeruli of type 2 diabetic Zucker diabetic fatty (ZDF) rats. RESULTS: By microarray profiling, we noted that GO-LDL treatment increased Axl receptor tyrosine kinase (Axl) mRNA expression (∼2.5-fold, p<0.05) compared with normal LDL (N-LDL) treatment in mesangial cells. Treatment with GO-LDL also increased the protein levels of Axl and its ligand Gas6 as measured by Western blotting. These increases were inhibited by neutralising Axl receptor-specific antibody. Silencing Gas6 by siRNA inhibited GO-LDL-induced Axl expression in mesangial cells. Axl and Gas6 protein were also increased in cells cultured in high glucose (30 mM) or methylglyoxal (200 µM). Gas6 treatment increased the expression and secretion of TGF-β1 protein, a key regulator of extracellular matrix expression in the glomeruli of diabetic kidneys. Immunohistochemical analyses of glomeruli from 20-week-old ZDF rats exhibited increased Axl protein expression. Rottlerin, a selective PKC-δ inhibitor, completely blocked Gas6-induced TGF-β1 expression. CONCLUSIONS/INTERPRETATION: These data suggest that LDL modified by glycoxidation may mediate Axl/Gas6 pathway activation, and this mechanism may play a significant role in the pathogenesis of diabetic nephropathy. Public Library of Science 2012-11-30 /pmc/articles/PMC3511478/ /pubmed/23226259 http://dx.doi.org/10.1371/journal.pone.0050297 Text en © 2012 Kim et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kim, Young Sook Jung, Dong Ho Sohn, Eunjin Kim, Junghyun Kim, Jin Sook Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells |
title | Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells |
title_full | Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells |
title_fullStr | Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells |
title_full_unstemmed | Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells |
title_short | Glycoxidised LDL Induced the Upregulation of Axl Receptor Tyrosine Kinase and Its Ligand in Mouse Mesangial Cells |
title_sort | glycoxidised ldl induced the upregulation of axl receptor tyrosine kinase and its ligand in mouse mesangial cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511478/ https://www.ncbi.nlm.nih.gov/pubmed/23226259 http://dx.doi.org/10.1371/journal.pone.0050297 |
work_keys_str_mv | AT kimyoungsook glycoxidisedldlinducedtheupregulationofaxlreceptortyrosinekinaseanditsligandinmousemesangialcells AT jungdongho glycoxidisedldlinducedtheupregulationofaxlreceptortyrosinekinaseanditsligandinmousemesangialcells AT sohneunjin glycoxidisedldlinducedtheupregulationofaxlreceptortyrosinekinaseanditsligandinmousemesangialcells AT kimjunghyun glycoxidisedldlinducedtheupregulationofaxlreceptortyrosinekinaseanditsligandinmousemesangialcells AT kimjinsook glycoxidisedldlinducedtheupregulationofaxlreceptortyrosinekinaseanditsligandinmousemesangialcells |