Transgene of MIF induces podocyte injury and progressive mesangial sclerosis in the mouse kidney |
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Authors: | Sasaki Satoshi Nishihira Jun Ishibashi Teruo Yamasaki Yoshiki Obikane Katsuyuki Echigoya Masayo Sado Yoshikazu Ninomiya Yoshifumi Kobayashi Kunihiko |
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Institution: | Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. sasak002@med.hokudai.ac.jp |
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Abstract: | BACKGROUND: Recent evidence suggests that macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in glomerulonephritis. Renal expression of MIF is up-regulated in infiltrating and intrinsic renal cells, which include glomerular epithelial cells. The aim of the current study was to further clarify the role of MIF produced by podocytes in the process of renal disease. METHODS: We generated transgenic mice carrying a murine MIF cDNA driven by cytomegalovirus enhancer and beta-actin/beta-globin promoter, a hybrid promoter transactivated in podocytes in vivo. RESULTS: MIF expression was markedly up-regulated in podocytes in neonatal and adult transgenic kidneys. A longitudinal study of the MIF transgenic mice demonstrated a progressive matrix increase in mesangium accompanied by collagen IV accumulation, representing no significant glomerular cell hypercellularity. The glomeruli in transgenic kidney were not accompanied by influx of macrophages and T cells at the early stage of disease progression. Although a significant number of the mice showing higher expression of MIF died from renal failure at 8 weeks, most of them survived with significant proteinuria and progressive renal failure. Podocytes of transgenic mice frequently underwent characteristic ultrastructural changes, such as cell flattening, contracted foot processes, and villous transformation. In addition, immunohistochemical expression of synaptopodin, an actin-associated protein distributed in differentiated podocyte foot process, was significantly attenuated in transgenic kidney. CONCLUSION: Our results indicate that podocyte-expressed MIF could induce an injury of podocytes themselves, thereby accelerating the progression of glomerulosclerosis and leading to end-stage renal failure. |
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