Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy

Jürgen Floege; Richard J. Johnson; Katherine Gordon; Ashio Yoshimura; Caryl Campbell; Luisa Iruela-Arispe; Charles E. Alpers; William G. Couser

doi:10.1038/ki.1992.321

Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy

Jürgen Floege^*, Richard J. Johnson, Katherine Gordon, Ashio Yoshimura, Caryl Campbell, Luisa Iruela-Arispe, Charles E. Alpers, William G. Couser

^*Corresponding author for this work

Cell & Developmental Biology

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Abstract

Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B₂-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B₂-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type 7 collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.

Original language	English (US)
Pages (from-to)	573-585
Number of pages	13
Journal	Kidney international
Volume	42
Issue number	3
DOIs	https://doi.org/10.1038/ki.1992.321
State	Published - Sep 1992

Funding

Acknowledgments This study was supported by U.S. Public Health Service grants DK 39068, DK 43422, DK 34198, DK 07467, DK 40802, a grant from the Northwest Kidney Foundation, a grant from the American Heart Association (Washington Affiliate 9l-WA-l03) to L. Iruela-Arispe, and by a post-doctoral stipend of the Deutsche Forschungsgemeinschaft to J. Floege.

ASJC Scopus subject areas

Nephrology

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10.1038/ki.1992.321

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@article{5210b129e57744ddbe7a6aa7ac4a4c3a,

title = "Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy",

abstract = "Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B2-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B2-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type 7 collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.",

author = "J{\"u}rgen Floege and Johnson, {Richard J.} and Katherine Gordon and Ashio Yoshimura and Caryl Campbell and Luisa Iruela-Arispe and Alpers, {Charles E.} and Couser, {William G.}",

note = "Funding Information: Acknowledgments This study was supported by U.S. Public Health Service grants DK Funding Information: 39068, DK 43422, DK 34198, DK 07467, DK 40802, a grant from the Northwest Kidney Foundation, a grant from the American Heart Association (Washington Affiliate 9l-WA-l03) to L. Iruela-Arispe, and by a post-doctoral stipend of the Deutsche Forschungsgemeinschaft to J. Floege.",

year = "1992",

month = sep,

doi = "10.1038/ki.1992.321",

language = "English (US)",

volume = "42",

pages = "573--585",

journal = "Kidney international",

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publisher = "Elsevier B.V.",

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T1 - Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy

AU - Floege, Jürgen

AU - Johnson, Richard J.

AU - Gordon, Katherine

AU - Yoshimura, Ashio

AU - Campbell, Caryl

AU - Iruela-Arispe, Luisa

AU - Alpers, Charles E.

AU - Couser, William G.

N1 - Funding Information: Acknowledgments This study was supported by U.S. Public Health Service grants DK Funding Information: 39068, DK 43422, DK 34198, DK 07467, DK 40802, a grant from the Northwest Kidney Foundation, a grant from the American Heart Association (Washington Affiliate 9l-WA-l03) to L. Iruela-Arispe, and by a post-doctoral stipend of the Deutsche Forschungsgemeinschaft to J. Floege.

PY - 1992/9

Y1 - 1992/9

N2 - Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B2-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B2-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type 7 collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.

AB - Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B2-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B2-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type 7 collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.

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Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy

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