Document Detail


Type VIII collagen modulates TGF-β1-induced proliferation of mesangial cells.
MedLine Citation:
PMID:  21372207     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mesangial cells in diabetic mice and human kidneys with diabetic nephropathy exhibit increased type VIII collagen, a nonfibrillar protein that exists as a heterodimer composed of α1(VIII) and α2(VIII), encoded by Col8a1 and Col8a2, respectively. Because TGF-β1 promotes the development of diabetic glomerulosclerosis, we studied whether type VIII collagen modulates the effects of TGF-β1 in mesangial cells. We obtained primary cultures of mesangial cells from wild-type, doubly heterozygous (Col8a1(+/-)/Col8a2(+/-)), and double-knockout (Col8a1(-/-)/Col8a2(-/-)) mice. TGF-β1 bound normally to double-knockout mesangial cells. In wild-type mesangial cells, TGF-β1 inhibited proliferation, but in double-knockout cells, it stimulated proliferation, promoted cell cycle progression, and reduced apoptosis; we could reverse this effect by reconstituting α1(VIII). Furthermore, in wild-type cells, TGF-β1 mainly stimulated the Smad pathways, whereas in double-knockout cells, it activated the MAPK and PI3K/Akt pathways and induced expression of fibroblast growth factor 21 (FGF21). Inhibiting FGF21 expression by either interfering with activation of the MAPK and PI3K/Akt pathways or by FGF21 siRNA attenuated the TGF-β1-induced proliferation of double-knockout mesangial cells. In vivo, diabetic double-knockout mice had significantly higher expression of renal FGF21 mRNA and protein compared with diabetic wild-type mice. Immunohistochemistry revealed strong expression of FGF21 in both glomerular (mesangial) and tubular cells of diabetic mice. Taken together, these data suggest that type VIII collagen significantly modulates the effect of TGF-β1 on mesangial cells and may therefore play a role in the pathogenesis of diabetic nephropathy.
Authors:
Ivonne Loeffler; Ulrike Hopfer; Dirk Koczan; Gunter Wolf
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-03
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  22     ISSN:  1533-3450     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-01     Completed Date:  2011-05-26     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  649-63     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 by the American Society of Nephrology
Affiliation:
Department of Internal Medicine III, University of Jena, Erlanger Allee 101, D-07740 Jena, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects,  physiology
Cell Cycle / drug effects,  physiology
Cell Proliferation / drug effects*
Cells, Cultured
Collagen Type VIII / genetics,  metabolism*
Diabetes Mellitus, Experimental / metabolism,  pathology,  physiopathology
Diabetic Nephropathies / metabolism,  pathology,  physiopathology
Disease Models, Animal
Fibroblast Growth Factors / metabolism
Mesangial Cells / drug effects,  metabolism*,  pathology*
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase Kinases / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Streptozocin
Transforming Growth Factor beta1 / pharmacology*,  physiology
Chemical
Reg. No./Substance:
0/Collagen Type VIII; 0/Transforming Growth Factor beta1; 0/fibroblast growth factor 21; 18883-66-4/Streptozocin; 62031-54-3/Fibroblast Growth Factors; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases
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