Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in experimental glomerulonephritis in mice.
The role of thrombospondin 2 (TSP2) was investigated in an anti-glomerular basement membrane (GBM) nephritis model that compared TSP2-null mice with wild-type (WT) controls. TSP2-null mice were analyzed for kidney function, renal cortical matrix expansion, influx of inflammatory cells, proliferation, and apoptosis, as well as for capillary rarefaction after induction of anti-GBM disease. Whereas the renal cortex of normal control WT mice did not show any detectable TSP2 staining above background, TSP2 protein expression was clearly upregulated in anti-GBM disease. TSP2 deficiency led to an accelerated and enhanced inflammatory response, as indicated by the influx of CD4(+) and CD8a(+) cells and monocytes/macrophages. Glomerular fibrin deposition and a matrix-remodeling response were also observed, as indicated by collagens I and IV staining and a proliferative response within the renal interstitium. These changes were accompanied by increased matrix metalloproteinase 2 activity and enhanced alpha-smooth muscle actin staining in the TSP2-null mice. Neither a compensatory increase in TSP1 nor increased phosphorylation of Smad 2/3, an indicator for TGF-beta activity, was observed. The proliferative response of the peritubular endothelium was accelerated and enhanced, leading to a reversal of capillary rarefaction in TSP2-null mice, whereas interstitial cell death was equivalent to that in WT mice. In conclusion, the lack of the matricellular protein TSP2 in mice accelerates and enhances several responses to renal injury and reveals an important role for TSP2 as a major endogenous antiangiogenic and matrix metalloproteinase 2-regulating factor in renal disease.
Daniel
Christoph
C
Department of Nephrology and Hypertension, Universität Erlangen-Nürnberg, Loschgestrasse 8, 91054 Erlangen, Germany.
Amann
Kerstin
K
Hohenstein
Bernd
B
Bornstein
Paul
P
Hugo
Christian
C
D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D005337:Fibrin / Q000378:metabolism; D050533:Glomerular Basement Membrane / Q000378:metabolism; D005921:Glomerulonephritis / Q000378:metabolism / Q000503:physiopathology*; D007249:Inflammation / Q000378:metabolism; D007672:Kidney Cortex / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019699:Thrombospondins / Q000172:deficiency / Q000378:metabolism*; D000099262:Thrombospondin 2
D020533:Angiogenesis Inhibitors; D015815:Cell Adhesion Molecules; D005337:Fibrin; D020778:Matrix Metalloproteinase 2; D019699:Thrombospondins; D000099262:Thrombospondin 2