Abstract
Mesangial cell proliferation is a significant event in the development of progressive glomerular injuries. However, the issue of how cell proliferation is involved in the development of glomerulosclerosis is unclear. Recently, we showed that the overexpression of type IV collagen (Col IV), a major component of mesangial extracellular matrix, is transcriptionally regulated by Smad1 in diabetic glomerulosclerosis. In this study, we have demonstrated the effect of the administration of an anti-platelet-derived growth factor (PDGF) beta-receptor antibody (APB5) blocking activation by the PDGF-B chain on rat glomerulonephritis and have examined the signaling pathways that regulate both glomerular cell proliferation and glomerulosclerosis in vivo and in vitro. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, mesangial cell proliferation and the expression of Col IV peaked at day 6. Immunohistochemical staining for the expression of Smad1, phospho-Smad1 (pSmad1), and phospho-STAT3 (pSTAT3) revealed that the peak for glomerular Smad1 expression occurred at day 6, consistent with the peak for mesangial proliferation. The expression of pSmad1 was up-regulated at day 1, and the peak for glomerular pSmad1 expression occurred at day 4 of the disease. When treated with APB5, both mesangial proliferation and sclerosis were reduced significantly. The expression of Smad1, pSmad1, and pSTAT3 was also significantly reduced by the administration of APB5. PDGF induced both mesangial cell replication and Col IV synthesis in association with an increased expression of pSTAT3 and pSmad1 on cultured mesangial cells. In addition, APB5 reduced mesangial cell proliferation in association with decreased pSmad1, pSTAT3, and Col IV protein expressions in vitro. The introduction of dominant negative STAT3 significantly decreased the expression of Col IV in cultured mesangial cells. These data suggest that the activation of STAT3 and Smad1 participates in the developing process of glomerulosclerosis in experimental glomerulonephritis.
Highlights
Mesangial cell proliferation is a significant event in the development of progressive glomerular injuries
Col IV is a major component of expanded ECM in glomerular diseases, but the molecular mechanism of regulating Col IV gene transcription had not been cleared until our recent report in which we showed that Smad1 transcriptionally regulates the overexpression of Col IV in diabetic nephropathy [8]
We have proposed a new direction of research concerning the pathogenesis and a therapeutic approach for chronic glomerulonephritis and diabetic nephropathy, which are major problems in the 21st century
Summary
Mesangial cell proliferation is a significant event in the development of progressive glomerular injuries. The introduction of dominant negative STAT3 significantly decreased the expression of Col IV in cultured mesangial cells These data suggest that the activation of STAT3 and Smad participates in the developing process of glomerulosclerosis in experimental glomerulonephritis. Both mesangial cell proliferation and glomerulosclerosis are major important pathological features in progressive glomerular damage. Smad directly transduces signals to downstream target genes that are related to renal damage such as osteopontin [9], inhibition of differentiation [10], and type I collagen [11] and is critically important for the development of kidney disease [12] These findings suggest that Smad is a critical transcriptional factor in the progression of glomerulosclerosis. Nakashima et al [14] report that transcriptional coactivator p300 physically interacts with STAT3 and Smad, followed by the subsequent activation of the target gene transcription in
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