Abstract
Connective tissue growth factor (CTGF) coordinates the signaling of growth factors and promotes fibrosis. Neonatal death of systemic CTGF knockout (KO) mice has hampered analysis of CTGF in adult renal diseases. We established 3 types of CTGF conditional KO (cKO) mice to investigate a role and source of CTGF in anti-glomerular basement membrane (GBM) glomerulonephritis. Tamoxifen-inducible systemic CTGF (Rosa-CTGF) cKO mice exhibited reduced proteinuria with ameliorated crescent formation and mesangial expansion in anti-GBM nephritis after induction. Although CTGF is expressed by podocytes at basal levels, podocyte-specific CTGF (pod-CTGF) cKO mice showed no improvement in renal injury. In contrast, PDGFRα promoter-driven CTGF (Pdgfra-CTGF) cKO mice, which predominantly lack CTGF expression by mesangial cells, exhibited reduced proteinuria with ameliorated histological changes. Glomerular macrophage accumulation, expression of Adgre1 and Ccl2, and ratio of M1/M2 macrophages were all reduced both in Rosa-CTGF cKO and Pdgfra-CTGF cKO mice, but not in pod-CTGF cKO mice. TGF-β1-stimulated Ccl2 upregulation in mesangial cells and macrophage adhesion to activated mesangial cells were decreased by reduction of CTGF. These results reveal a novel mechanism of macrophage migration into glomeruli with nephritis mediated by CTGF derived from mesangial cells, implicating the therapeutic potential of CTGF inhibition in glomerulonephritis.
Highlights
IntroductionAnti-glomerular basement membrane glomerulonephritis (anti-GBM nephritis) is a life-threatening disease[1,2]
Anti-glomerular basement membrane glomerulonephritis is a life-threatening disease[1,2]
We investigated a role of CTGF in a mouse model of anti-GBM nephritis, using three types of conditional CTGF KO mice
Summary
Anti-glomerular basement membrane glomerulonephritis (anti-GBM nephritis) is a life-threatening disease[1,2]. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and transforming growth factor-β(TGF-β) are reported to be major mediators of progressive anti-GBM nephritis[3,4,5]. Identification of the specific glomerular cell types responsible for pathological CTGF expression has remained unanswered. We generated tamoxifen-inducible CTGF conditional KO (Rosa-CTGF cKO) mice to investigate importance of CTGF in the progression of anti-GBM nephritis, since conventional systemic CTGF KO mice die shortly after birth because of respiratory failure caused by skeletal defects[16]. We generated podocyte-specific CTGF conditional KO (pod-CTGF cKO) mice. We established PDGFRαpromoter-driven CTGF conditional KO (Pdgfra-CTGF cKO) mice, which predominantly lack CTGF expression in mesangial cells of the glomeruli, to investigate the cell type-specific contribution of CTGF in anti-GBM nephritis model
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