Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis

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.

Podocyte-specific knockout of the neonatal Fc receptor (FcRn) results in differential protection depending on the model of immune-mediated kidney disease

“…Of note, although the anti-GBM model resulted in significant albuminuria in both control and podFcRn KO mice, the percentage of crescents seen in the control mice was relatively low. These findings are in accord with some other studies of this model in mice, (49)(50)(51)(52) making this model less ideal to study immune mediated kidney disease.…”

A CTGF-YAP regulatory pathway is essential for angiogenesis and barriergenesis in the retina

“…7D-E). Quantitative real time PCR for PLVAP, one of the most important endothelial genes encoding a structural protein of fenestral and stomatal diaphragms (van der Wijk et al, 2019), showed that the low PLVAP levels in WT mouse retinas were not affected by either loss of CTGF function or YAP reexpression ( Fig. 7F) suggesting that CTGF signals do not target transcellular transport proteins.…”

“…In the retina, angiogenesis occurs during postnatal stages when ECs from the brain invade the optic nerve, emerge from it and spread over and within the retinal neuroepithelium (Fruttiger, 2007). This angiogenic process is coordinated with the simultaneous formation of a blood retinal barrier wherein the paracellular permeability between adjacent ECs and transcellular transport across ECs are tightly regulated by junctional protein complexes and transporter proteins, respectively (van der Wijk et al, 2019). Cells within the cohesive vascular wall have cadherin-based adhesions at cell-cell junctions and integrin-based focal adhesions to cell-extracellular matrix (ECM) contacts.…”

“…In adults, CTGF plays an important role in wound repair and CTGF protein levels correlate with many vascular and inflammatory diseases such as arthritis, diabetic nephropathy and retinopathy (Chintala et al, 2012;Leask et al, 2002;Nguyen et al, 2008;Praidou et al, 2010;Tang et al, 2018). In a rat model of glomerulonephritis, CTGF levels were elevated in areas of crescentic extracapillary proliferation, periglomerular fibrosis, and in interstitial foci (Gupta et al, 2000;Toda et al, 2017). While these in vivo studies suggested a potentially important role of CTGF in physiological and pathological angiogenesis, the specific function and mechanisms whereby CTGF regulates blood vessel development and function remain to be investigated.…”

Ablation of Myeloid Cell MRP8 Ameliorates Nephrotoxic Serum-induced Glomerulonephritis by Affecting Macrophage Characterization through Intraglomerular Crosstalk

“…Meanwhile, focusing on the glomerular intrinsic cells, we demonstrated a novel role of mesangial cells in glomerular injury through enhancing MRP8 expression and the following characterization changes in Mφ. We previously reported that mesangial cells could be important in Mφ infiltration during glomerulonephritis in a CTGF-dependent manner 41 . Therefore, we focused on the intraglomerular crosstalk between mesangial cells and Mφ, which induces the expression of MRP8 and M1 dominancy which results in aggravation of kidney injury.…”