Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-beta activation.

Full Abstract

We recently identified thrombospondin-2 (TSP-2) as an endogenous regulator of matrix remodelling and inflammation in experimental kidney disease by studying TSP-2-deficient mice. In this study, we asked whether systemic TSP-2 overexpression via thigh muscle transfection is able to ameliorate the time course of the anti-Thy1 glomerulonephritis model. After induction of anti-Thy1 nephritis, rats were transfected either with an overexpression plasmid for TSP-2 or lacZ as a control. Biopsies, urine, and blood samples were taken on days 1, 3, and 6 after disease induction. Muscular overexpression of TSP-2 reduced glomerular transforming growth factor (TGF)-beta activation and glomerular extracellular matrix formation as determined by collagen IV and fibronectin. In addition, activation of mesangial cells to the myofibroblast-like phenotype was also significantly decreased in TSP-2-overexpressing animals. TSP-2 overexpression inhibited both glomerular endothelial and mesangial cell proliferation, resulting in a reduced glomerular cell number and glomerular tuft area. The inflammatory response, as monitored by T cells and antigen-presenting cells, was reduced significantly by TSP-2 overexpression, but influx of macrophages was unchanged. These data demonstrate TSP-2 as a potential therapeutic agent to inhibit the glomerular proliferative and inflammatory response as well as TGF-beta activation and extracellular matrix accumulation in experimental mesangial proliferative glomerulonephritis.

Author information

Author/s: Daniel, Christoph (C); Wagner, Andrea (A); Hohenstein, Bernd (B); Hugo, Christian (C);

Affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany. Christoph.Daniel(-atsign-)uk-erlangen.de

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol), published in United States. (Language: eng)

Reference: 2009-Nov; vol 297 (issue 5) : pp F1299-309

Dates: Created 2009/11/02; Completed 2009/11/17;

PMID: 19726547, status: MEDLINE (last retrieved date: 11/17/2009)

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals
Blotting, Western
Cell Proliferation - drug effects
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Extracellular Matrix - metabolism; pathology
Fibroblasts - physiology
Fibronectins - biosynthesis; genetics
Fibrosis - drug therapy
Gene Expression - physiology
Gene Therapy
Glomerulonephritis - pathology; therapy

Glomerulonephritis - pathology; therapy
Immunohistochemistry
In Situ Nick-End Labeling
Inflammation - pathology; therapy
Kidney - pathology
Lac Operon - genetics
Matrix Metalloproteinase 2 - biosynthesis; genetics
Mice
Rats
Thrombospondins - biosynthesis; genetics; physiology
Transfection
Transforming Growth Factor beta - metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Fibronectins (0) ; Thrombospondins (0) ; Transforming Growth Factor beta (0) ; thrombospondin 2 (0) ; Matrix Metalloproteinase 2 (EC 3.4.24.24)

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