Source:http://linkedlifedata.com/resource/pubmed/id/20661225
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1
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pubmed:dateCreated |
2010-12-29
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pubmed:abstractText |
The nicotinic acetylcholine receptor ?1 (nAChR?1) was investigated as a potential proinflammatory molecule in the kidney, given a recent report that it is an alternative urokinase plasminogen activator (uPA) receptor, in addition to the classical receptor uPAR. Two animal models and in vitro monocyte studies were involved: (1) In an ApoE(-/-) mouse model of chronic kidney disease, glomerular-resident cells and monocytes/macrophages were identified as the primary cell types that express nAChR?1 during hypercholesterolemia/uninephrectomy-induced nephropathy. Silencing of the nAChR?1 gene for 4 months (6 months on Western diet) prevented the increases in renal monocyte chemoattractant protein-1 and osteopontin expression levels and F4/80+ macrophage infiltration compared with the nonsilenced mice. These changes were associated with significantly reduced transforming growth factor-?1 mRNA (50% decrease) and ? smooth muscle actin-positive (?SMA+) myofibroblasts (90% decrease), better glomerular and tubular basement membranes (GBM/TBM) preservation (threefold less disintegration), and better renal function preservation (serum creatinine 40% lower) in the nAChR?1-silenced mice. The nAChR?1 silencing was also associated with significantly reduced renal tissue calcium deposition (78% decrease) and calpain-1 (but not calpain-2) activation (70% decrease). (2) The nAChR?1 was expressed in vitro by mouse monocyte cell line WEHI-274.1. The silencing of nAChR?1 significantly reduced both calpain-1 and -2 activities, and reduced the degradation of the calpain substrate talin. (3) To further explore the role of calpain-1 activity in hypercholesterolemic nephropathy, disease severities were compared in CAST(-/-)ApoE(-/-) (calpain overactive) mice and ApoE(-/-) mice fed with Western diet for 10 months (n=12). Macrophages were the main cell type of renal calpain-1 production in the model. The number of renal F4/80+ macrophages was 10-fold higher in the CAST(-/-)ApoE(-/-) mice (P<0.05), and was associated with a significantly higher level of ?SMA+ cells, increased GBM/TBM destruction, and higher serum creatinine levels. Our studies suggest that the receptor nAChR?1 is an important regulator of calpain-1 activation and inflammation in the chronic hypercholesterolemic nephropathy. This new proinflammatory pathway may also be relevant to other disorders beyond hyperlipidemic nephropathy.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Actins,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Differentiation,
http://linkedlifedata.com/resource/pubmed/chemical/Apolipoproteins E,
http://linkedlifedata.com/resource/pubmed/chemical/CHRNA1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Calpain,
http://linkedlifedata.com/resource/pubmed/chemical/Capn1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Nicotinic,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta1,
http://linkedlifedata.com/resource/pubmed/chemical/calpastatin,
http://linkedlifedata.com/resource/pubmed/chemical/monocyte-macrophage...
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1530-0307
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:volume |
91
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
106-23
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pubmed:dateRevised |
2011-10-6
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pubmed:meshHeading |
pubmed-meshheading:20661225-Actins,
pubmed-meshheading:20661225-Animals,
pubmed-meshheading:20661225-Antigens, Differentiation,
pubmed-meshheading:20661225-Apolipoproteins E,
pubmed-meshheading:20661225-Blotting, Northern,
pubmed-meshheading:20661225-Blotting, Western,
pubmed-meshheading:20661225-Calcium-Binding Proteins,
pubmed-meshheading:20661225-Calpain,
pubmed-meshheading:20661225-Cell Line,
pubmed-meshheading:20661225-Female,
pubmed-meshheading:20661225-Hypercholesterolemia,
pubmed-meshheading:20661225-Inflammation,
pubmed-meshheading:20661225-Kidney,
pubmed-meshheading:20661225-Kidney Diseases,
pubmed-meshheading:20661225-Macrophages,
pubmed-meshheading:20661225-Male,
pubmed-meshheading:20661225-Mice,
pubmed-meshheading:20661225-Mice, 129 Strain,
pubmed-meshheading:20661225-Mice, Inbred C57BL,
pubmed-meshheading:20661225-Mice, Knockout,
pubmed-meshheading:20661225-Monocytes,
pubmed-meshheading:20661225-Nephrectomy,
pubmed-meshheading:20661225-RNA Interference,
pubmed-meshheading:20661225-Receptors, Nicotinic,
pubmed-meshheading:20661225-Transforming Growth Factor beta1
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pubmed:year |
2011
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pubmed:articleTitle |
Nicotinic acetylcholine receptor ?1 promotes calpain-1 activation and macrophage inflammation in hypercholesterolemic nephropathy.
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pubmed:affiliation |
Division of Nephrology, Seattle Children's Hospital Research Institute, Department of Pediatrics, University of Washington, Seattle, WA 98101, USA. MD6GZ@yahoo.com
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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