Induction and Coexpression of Latent Transforming Growth Factor β-Binding Protein-1 and Fibrillin-1 in Experimental Glomerulonephritis

Abstract

Background: Latent transforming growth factor-β-binding protein 1 (LTBP-1) and fibrillin-1 were shown to colocalize and interact in the extracellular matrix of the skin and vasculature. This interaction may regulate transforming growth factor-β (TGF-β) activity. TGF-β is an important progression factor for glomerular diseases. We hypothesized that LTBP-1 and fibrillin-1 are coexpressed in the glomerulus and upregulated during glomerulonephritis. Methods: Acute anti-Thy1.1 glomerulonephritis was induced with a single intravenous injection (1 mg/kg body weight) of a monoclonal anti-Thy1.1 antibody in rats. Real-time RT-PCR and immunohistochemical analyses for LTBP-1 and fibrillin-1 were performed. Results: Induction of glomerular LTBP-1 mRNA was detected on day 2 of disease, while mRNA for fibrillin-1 was already upregulated 1 day after induction of disease. Both LTBP-1 and fibrillin-1 showed a mesangial distribution. An expansion of the LTBP-1 and fibrillin-1-positive mesangial area was seen on day 6 of disease, when transient matrix accumulation was most prominent. On day 12 of disease, glomerular LTBP-1 and fibrillin-1 immunoreactivities had returned to control levels. In serial sections, some colocalization of LTBP-1 and fibrillin-1 was detected in control as well as in nephritic glomeruli. Conclusion: Mesangial expression of LTBP-1 and fibrillin-1 is induced early in experimental nephritis and LTBP-1 and fibrillin-1 are partially colocalized in the nephritic glomerulus. An interaction of these molecules could stabilize latent TGF-β complexes and thus attenuate the activation of TGF-β during this self-limited glomerular disease.

Fibrillin-1 and alpha8 integrin are co-expressed in the glomerulus and interact to convey adhesion of mesangial cells

“…Interactions of fibrillin-1 with LTBP-1, the latency-associated TGFb binding protein, are known to regulate the activity of profibrotic TGFb 19 , which is known to be relevant in the vasculature, as Marfan patients which frequently suffer from aortic aneurysms, were shown to have a dysregulation of TGFb activation. 20 Coexpression of LTBP-1 and fibrillin-1 in the glomerulus and induction of both in Thy1.1 nephritis was also demonstrated, 21 arguing for a role of fibrillin-1 in the regulation of TGFb activity in the glomerulus. Fibrillin-1 might therefore serve antifibrotic functions by reducing profibrotic active TGFb.…”

Direct Interaction of CD40 on Tumor Cells with CD40L on T Cells Increases the Proliferation of Tumor Cells by Enhancing TGF-β Production and Th17 Differentiation

“…Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine that controls multiple cellular responses including the induction of cell growth inhibition, differentiation, cellular senescence, wound healing and apoptosis [ 13 ]. TGF-β cannot bind to its receptors in its latent form which is regulated by latency-associated protein and latent- TGF-β binding protein [ 14 ]. In vitro, these factors can be inactivated by extreme pH or heat, or by several proteases [ 15 ].…”

Role of TGF-ß in Mesangial Matrix Accumulation in Chronic Progressive Glomerular Disease

“…Intense mesangial immunostaining for LTBP-1 is observed in anti-Thy1.1 nephritis associated with severe but transient mesangial matrix accumulation (Porst et al 2006). In rats with anti-Thy1.1 nephritis, active TGF-ß1-positive area/glomerulus was 18%, while treatment with antisense TSP-1 oligodeoxynucleotides reduced it to 9% (Daniel et al 2003).…”