title: Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-beta activation.
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.
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany. Christoph.Daniel@uk-erlangen.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.forename: Andrea
authors.initials: A
authors.lastname: Wagner
authors.forename: Bernd
authors.initials: B
authors.lastname: Hohenstein
authors.forename: Christian
authors.initials: C
authors.lastname: Hugo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000502:physiology; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis / Q000188:drug therapy; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy; D005921:Glomerulonephritis / Q000473:pathology / Q000628:therapy*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology / Q000628:therapy*; D007668:Kidney / Q000473:pathology; D007763:Lac Operon / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D051381:Rats; D019699:Thrombospondins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099262:Thrombospondin 2
chemical_list: D005353:Fibronectins; D020778:Matrix Metalloproteinase 2; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D000099262:Thrombospondin 2