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-beta) 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-beta 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 alpha- and beta-receptor (beta-R) and TGF-beta1 mRNA were analyzed by in situ hybridization. Expression of alpha smooth muscle actin (alphaSMA), 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 beta-R or TGF-beta1 mRNA.

RESULTS:

Increased numbers of proliferating glomerular cells appeared early in the disease course, associated with de novo expression of alphaSMA. Expression of PDGF B-chain and beta-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-beta1 mRNA expression paralleled the deposition of type IV collagen. A significant proportion of Mac-2 positive macrophages expressed TGF-beta1 mRNA, while only a small percentage of glomerular macrophages expressed PDGF B-chain mRNA. No PDGF beta-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 beta-R and TGF-beta1. 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.

• Authors: Sekiko Taneda, Kelly L Hudkins, Yan Cui, Andrew G Farr, Charles E Alpers, Stephan Segerer
• Journal: Kidney international (Kidney Int) Vol. 63 Issue 2 Pg. 576-90 (Feb 2003) ISSN: 0085-2538 [Print] United States
• PMID: 12631122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Actins
• Collagen Type IV
• Cytokines
• Laminin
• Proto-Oncogene Proteins c-sis
• RNA, Messenger
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Tgfb1 protein, rat
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Receptor, Platelet-Derived Growth Factor beta
• Thymic Stromal Lymphopoietin
• TSLP protein, mouse

Topics

• Actins (metabolism)
• Animals
• Cell Division
• Collagen Type IV (metabolism)
• Cryoglobulinemia (metabolism, pathology)
• Cytokines (genetics, metabolism)
• Extracellular Matrix (metabolism)
• Kidney Glomerulus (metabolism, pathology)
• Laminin (metabolism)
• Macrophages (metabolism, pathology)
• Mice
• Mice, Transgenic (genetics)
• Muscle, Smooth (metabolism)
• Proto-Oncogene Proteins c-sis (genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Transforming Growth Factor beta1
• Thymic Stromal Lymphopoietin