BMP4 in Diabetic Nephropathy

Podocyte injury and loss have been indicated as constituting the crucial pathogenesis of glomerular injury ; however, it remains necessary to elucidate the detailed molecular mechanisms and cell-to-cell response because multiple factors may cause podocyte injury. In the glomerulus, three kinds of cells (endothelial, mesangial, and parietal epithelial) react to podocyte injury. Endothelial and mesangial cells are connected with podocyte cells across the glomerular basement membrane. However, the detailed mechanisms regarding the interaction of the mesangium and podocyte injury are unclear. Diabetic nephropathy is characterized by mesangial matrix expansion caused by an excessive deposition of extracellular matrix proteins in the mesangial area, which can be observed through the increased expression of type IV collagen. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the effect of BMP4 was investigated in vitro and in vivo using streptozotocin (STZ)-induced and Bmp4 heterozygous knockout (Bmp4+/-) diabetic mice or podocyte-specific Bmp4 knockout mice, and Bmp4-induced or podocyte-specific transgenic mice. BMP4 positive area and mesangial area fraction showed positively correlation. Furthermore, mesangial area fraction was significantly and negatively correlated with,WT1-positive cell number, and nephrin-positive area. We also demonstrated that the induction of podocyte apoptosis by BMP4 may be mediated by p38 activation and that of caspase 3 through cleavage. In mesangial cells, BMP4 stimulation also induced phosphorylation of p38 and Smad1 and increased cleaved caspase 3, with similar significant inhibition of Smad1 activation and decreased cleaved caspase 3 mediated by dorsomorphin. These data suggest that the BMP4 signaling pathway plays important roles for the development of both podocyte injury and mesangial expansion in diabetic nephropathy

BMP4の機能調節は糖尿病性腎症及びポドサイト障害の治療につながる

Podocyte injury has been proposed to play an important role in diabetic nephropathy; however, its pathological mechanism remains unclear. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the molecular mechanism of podocyte injury, the effect of BMP4 was investigated using streptozotocin (STZ)- induced, Bmp4 heterozygous knockout (Bmp4+/−) and podocyte-specific Bmp4 knockout mice. Mice with STZ-induced diabetes exhibited glomerular matrix hyperplasia and decreased numbers of podocyte nucleus-specific WT1-positive cells. The number of podocytes and proteinuria were improved in both diabetic Bmp4 knockout mouse models compared to the effects observed in the control mice. The effect of BMP4 overexpression on Bmp4-induced or podocyte-specific transgenic mice was examined. Tamoxifen-induced Bmp4-overexpressing mice exhibited mesangial matrix expansion and decreased numbers of WT1-positive cells. Podocyte-specific Bmp4-overexpressing mice displayed increased kidney BMP4 expression and mesangial matrix expansion but decreased nephrin expression and numbers of WT1-positive cells. Both lines of Bmp4-overexpressing mice exhibited increased albuminuria. In cultured podocytes, BMP4 increased phospho-p38 levels. BMP4 decreased nephrin expression but increased cleaved caspase-3 levels. p38 suppression inhibited caspase-3 activation. Apoptosis was confirmed in STZ-diabetic glomeruli and Bmp4-overexpressing mice. Bmp4 +/− mice with diabetes displayed reduced apoptosis. Based on these data, the BMP4 signaling pathway plays important roles in the development of both podocyte injury and mesangial matrix expansion in diabetic nephropathy