Background: In a number of experimental models of nephropathy, heparin is renoprotective because it inhibits mesangial matrix synthesis and cell proliferation; in most of these models, glomerular macrophage infiltration has a pathogenic role. We investigated the hypothesis that heparin might also be renoprotective by modulating the macrophages in various ways in the chronic puromycin glomerulosclerosis model. Methods: We studied the effect of a 3 month course, two different dosages of a non-anticoagulant heparin by immunohistochemical evaluation of the number of macrophages (ED-1 positive cells) in glomeruli, as well as the expression and deposition of TGF-beta and latent TGF-beta binding protein in foam cells and mesangial matrix. Results: The renoprotective effect of heparin in this model was confirmed by our observation of lower urine protein and albumin excretion, and a reduced glomerular sclerosis score. These effects were associated with the prevention of macrophage glomerular infiltration, and the inhibition of the TGF-beta axes in foam cells as shown by the reduction in cytoplasm immunostaining for TGF-beta and LTBP-1; heparin also reduced peri-macrophagic collagen IV deposition. Conclusions: The inhibition of TGF-beta in macrophages seems to be part of heparin general activities. The inhibitory effect of heparin on macrophage infiltration and TGF-beta synthesis in this renal disease model supports the notion that heparin and derived molecules constitute potentially useful therapeutic agents in nephropathies.
Heparin reduces glomerular infiltration and TGF-beta protein expression by macrophages in puromycin glomerulosclerosis
CEOL, MONICA;VIANELLO, DANIELA;ANGLANI, FRANCA;BONFANTE, LUCIANA;D'ANGELO, ANGELA;DEL PRETE, DORELLA;
2003
Abstract
Background: In a number of experimental models of nephropathy, heparin is renoprotective because it inhibits mesangial matrix synthesis and cell proliferation; in most of these models, glomerular macrophage infiltration has a pathogenic role. We investigated the hypothesis that heparin might also be renoprotective by modulating the macrophages in various ways in the chronic puromycin glomerulosclerosis model. Methods: We studied the effect of a 3 month course, two different dosages of a non-anticoagulant heparin by immunohistochemical evaluation of the number of macrophages (ED-1 positive cells) in glomeruli, as well as the expression and deposition of TGF-beta and latent TGF-beta binding protein in foam cells and mesangial matrix. Results: The renoprotective effect of heparin in this model was confirmed by our observation of lower urine protein and albumin excretion, and a reduced glomerular sclerosis score. These effects were associated with the prevention of macrophage glomerular infiltration, and the inhibition of the TGF-beta axes in foam cells as shown by the reduction in cytoplasm immunostaining for TGF-beta and LTBP-1; heparin also reduced peri-macrophagic collagen IV deposition. Conclusions: The inhibition of TGF-beta in macrophages seems to be part of heparin general activities. The inhibitory effect of heparin on macrophage infiltration and TGF-beta synthesis in this renal disease model supports the notion that heparin and derived molecules constitute potentially useful therapeutic agents in nephropathies.
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