DK-03-O01: Bench to Bedside Research on Type 1 Diabetes and its Complications; Topic: Transitional Projection on Prevention of Diabetic Nephropathy; Invited Resubmission of 1 R21 DK63360-01 Bone morphogenetic protein-7 (BMP7) is a kidney-expressed protein with novel therapeutic potential in diabetic nephropathy. Recent in-vitro studies by the PI indicate that BMP7 inhibits fibrogenesis in cultured renal cells. BMP7 is a member of the TGF-beta superfamily of cysteine-knot cytokines and appears to provide its anti-fibrogenic activity through antagonizing this latter TGF-beta. BMP7 is heavily expressed in normal kidney but its levels decrease in diabetes predating onset of glomerular sclerosis and tubulo-interstitial fibrosis. With the proposed in-vivo studies the investigators will carry the recent in-vitro findings forward to the more complex diabetic nephropathy animal model. We will test the hypothesis that renally expressed BMP7 reduces diabetes-induced injury to glomeruli and tubules and protects diabetic mice from glomerular and tubular injury and fibrogenesis. Thus, BMP7 may prevent diabetic nephropathy. This hypothesis will be tested in a recently developed, uniquely suited mouse model bearing a kidney-targeted BMP7-transgene and genetically similar, wild-type controls. BMP7 transgenic and wild-type mice will be made diabetic with streptozotocin, and non-diabetic, BMP7-transgenic and wild-type mice will serve as controls in prospective, long-term studies. Measurements of renal function will be made periodically, and biochemical and molecular studies will be performed on kidney preparations at 4, 8 and 12 months. Studies include assessments of renal function and albuminuria and differential expression of endogenous versus transgenic BMP7. Injury and apoptosis of podocytes and tubular epithelium, and extracellular matrix protein accumulation as well as levels and activity of fibrogenesis-regulating proteins will also be assessed. These measurements are made using appropriate and established, quantitative assays. The proposed in-vivo studies are a transitional step in the study of BMP7 as an endogenous, physiologically reno-protective protein. Moreover, BMP7 may become a novel avenue in the prevention and treatment of diabetic nephropathy.
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| Mitu, Grace M; Wang, Shinong; Hirschberg, Raimund (2007) BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury. Am J Physiol Renal Physiol 293:F1641-8 |
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| Wang, Shinong; Hirschberg, Raimund (2004) Bone morphogenetic protein-7 signals opposing transforming growth factor beta in mesangial cells. J Biol Chem 279:23200-6 |
