Universität zu Köln

Rubel, Diana, Frese, Jenny, Martin, Maria, Leibnitz, Alexander, Girgert, Rainer ORCID: 0000-0001-8210-242X, Miosge, Nicolai, Eckes, Beate, Mueller, Gerhard-Anton and Gross, Oliver (2014). Collagen receptors integrin alpha2beta1 and discoidin domain receptor 1 regulate maturation of the glomerular basement membrane and loss of integrin alpha2betal delays kidney fibrosis in COL4A3 knockout mice. Matrix Biol., 34. S. 13 - 22. AMSTERDAM: ELSEVIER. ISSN 1569-1802

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Abstract

Maturation of the glomerular basement membrane (GBM) is essential for maintaining the integrity of the renal filtration barrier. Impaired maturation causes proteinuria and renal fibrosis in the type IV collagen disease Alport syndrome. This study evaluates the role of collagen receptors in maturation of the GBM, matrix accumulation and renal fibrosis by using mice deficient for discoidin domain receptor 1 (DDR1), integrin subunit alpha 2 (ITGA2), and type IV collagen alpha 3 (COL4A3). Loss of both collagen receptors DDR1 and integrin alpha 2 beta 1 delays maturation of the GBM: due to a porous GBM filtration barrier high molecular weight proteinuria that more than doubles between day 60 and day 100. Thereafter, maturation of the GBM causes proteinuria to drop down to one tenth until day 200. Proteinuria and the porous GBM cause accumulation of glomerular and tubulointerstitial matrix, which both decrease significantly after GBM-maturation until day 250. In parallel, in a disease with impaired GBM-maturation such as Alport syndrome, loss of integrin alpha 2 beta 1 positively delays renal fibrosis: COL4A3(-/-) ITGA2(-/-) double knockouts exhibited reduced proteinuria and urea nitrogen compared to COL4A3(-/-)/ITGA2(-/-) and COL4A3(-/-)/ITGA2(+/+) mice. The double knockouts lived 20% longer and showed less glomerular and tubulointerstitial extracellular matrix deposition than the COL4A3(-/-) Alport mice with normal integrin alpha 2 beta 1 expression. Electron microscopy illustrated improvements in the glomerular basement membrane structure. MMP2, MMP9, MMP12 and TIMP1 were expressed at significantly higher levels (compared to wild-type mice) in COL4A3(-/-)/ITGA2(+/+) Alport mice, but not in COL4A3(+/+)/ITGA2(-/-) mice. In conclusion, the collagen receptors DDR1 and integrin alpha 2 beta 1 contribute to regulate GBM-maturation and to control matrix accumulation. As demonstrated in the type IV collagen disease Alport syndrome, glomerular cell-matrix interactions via collagen receptors play an important role in the progression of renal fibrosis. (C) 2014 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rubel, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Frese, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Martin, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Leibnitz, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Girgert, Rainer UNSPECIFIED orcid.org/0000-0001-8210-242X UNSPECIFIED Miosge, Nicolai UNSPECIFIED UNSPECIFIED UNSPECIFIED Eckes, Beate UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Gerhard-Anton UNSPECIFIED UNSPECIFIED UNSPECIFIED Gross, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-446133
DOI:	10.1016/j.matbio.2014.01.006
Journal or Publication Title:	Matrix Biol.
Volume:	34
Page Range:	S. 13 - 22
Date:	2014
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1569-1802
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IV COLLAGEN; ALPORT-SYNDROME; MOUSE; MECHANISMS; NETWORKS; INSIGHTS; BINDING Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44613