| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
We previously reported that BMP4 has an important role in the early development of urogenital system. In this study, we generated transgenic mice carrying either loss or gain of BMP4 function selectively in podocytes, Nephrin-Noggin and Nephrin-Bmp4 transgenic mice, respectively, to examine the role of BMP4 on glomerular morphogenesis. At birth, Nephrin-Noggin mice were found to have glomerular microaneurysms, collapsed glomerular capillary tufts, enlarged Bowman's capsules and decreased proximal tubule population. The latter two morphological phenotypes resembled that in podocyte-specific Vegf-A overexpressing mice reported earlier. By contrast, Nephrin-Bmp4 mice showed defective glomerular capillary formation which accompanies defects in endothelial and mesangial cells while podocytes were not appreciably affected, a phenotype similar to the podocyte-specific Vegf-A knockouts. In situ hybridization revealed that podocyte expression of Vegf appeared to be suppressed in Nephrin-Bmp4 mice, whereas intense signal was seen in Nephrin-Noggin mice. These findings appeared to suggest that BMP4 directly regulates Vegf expression in podocytes. However, in vitro studies with cultured podocytes or metanephroi found no effect of BMP4 or Noggin on podocyte expression of Vegf. In addition, phosphorylated Smads, mediators for BMP signaling, were present in endothelial and/or mesangial cells, but not in podocytes. Finally, at 10 months of age, massive mesangial expansion developed in all of the Nephrin-Noggin mice. The lesion was characterized by the accumulation of fibronectin, the phenotype similar to the diabetic nephropathy. These results suggest that endogenous BMP has an important role in normal capillary formation and regulation of the glomerular structural homeostasis.
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