Growth factor expression in a murine model of cryoglobulinemia

Abstract

Background. Increased expression of growth factors including platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) are thought to play pivotal roles during mesangial expansion and glomerulosclerosis. Thymic stromal lymphopoietin (TSLP) transgenic mice develop mixed cryoglobulinemia and a membranoproliferative glomerulonephritis (MPGN). Here we describe the renal expression of isoforms of PDGF and TGF-β in relation to changes in extracellular matrix (ECM) components and markers of cell proliferation and activation in this model. Methods. A total of 123 mice, including 61 TSLP transgenic mice and 62 wild-type controls, were sacrificed at defined intervals. PDGF-A chain, -B chain, PDGF α- and β-receptor (β-R) and TGF-β1 mRNA were analyzed by in situ hybridization. Expression of α smooth muscle actin (αSMA), collagen type I, collagen type IV, laminin, and a marker of proliferating cells (PCNA) were assessed by immunohistochemistry. Slides also were studied by combined immunohistochemistry and in situ hybridization with an antibody that recognizes monocytes/macrophage and with riboprobes that detect PDGF B-chain, PDGF β-R or TGF-β1 mRNA. Results. Increased numbers of proliferating glomerular cells appeared early in the disease course, associated with de novo expression of αSMA. Expression of PDGF B-chain and β-R mRNA was increased in the mesangium and in parietal epithelial cells of TSLP transgenic mice and correlated with the number of PCNA positive cells. Increased TGF-β1 mRNA expression paralleled the deposition of type IV collagen. A significant proportion of Mac-2 positive macrophages expressed TGF-β1 mRNA, while only a small percentage of glomerular macrophages expressed PDGF B-chain mRNA. No PDGF β-R mRNA expression by macrophages was detected. Conclusion. TSLP transgenic mice develop a membranoproliferative glomerulonephritis in which glomerular cell proliferation and matrix deposition are associated with an increased expression of PDGF B-chain, PDGF β-R and TGF-β1. These findings extend the paradigms covering these growth factors established in the rat Thy 1 model of mesangiolysis and repairs to a murine model of progressive glomerulonephritis closely resembling human MPGN.