Development of Specific Biomarker and Molecular Targeting Therapy for Diabetic Nephropathy by RAS-independent Pathway

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BMP4 directly regulated Smad1 signaling in vitro. Both BMP4 and phosphorylated Smad1 were expressed in association with mesangial matrix hyperplasia in diabetic kidney. BMP4 knock-in transgenic mice showed typical mesangial matrix increase as well as BMP4 expression after induction by tamoxifen. On the other hand, BMP4 knock-out (BMP4(+/-)) mice showed amelioration of glomerular matrix hyperplasia induced by streptozotocin. Furthermore, neutralizing antibody for BMP4 normalized glomerular matrix hyperplasia and phosphorylated Smad1 expression in glomeruli of diabetic mice. These results suggest that BMP4/Smad1 signaling plays the critical pathogenetic role for diabetic nephropathy.