Bone morphogenetic protein-7, BMP-7, is a critical renal morphogen that is required for development but continues to be expressed at high levels in adult renal tubular segments. Recent studies have demonstrated that BMP-7 prevents the tubulointerstitial nephritis associated with chronic renal injury. BMP-7 appears to function as a hormonal differentiation factor and one of its effects, as such, may be to suppress the transcription of genes activated by various renal injuries. This function would suggest strong therapeutic potential for such a hormone in its target tissues. The therapeutic targets of BMP-7 include the skeleton, the vasculature and the kidney. In the kidney, specific BMP-7 receptors are expressed in the collecting duct, proximal tubule and the glomerulus. The long-range objective of this application is to analyze the efficacy of BMP-7 in various forms of chronic kidney disease (CKD). The studies in the application will address two hypotheses. The first is that BMP-7 is an effective therapeutic agent in CKD. Since many forms of CKD are accompanied by a major tubulointerstitial component in their later stages, we propose that the usefulness of BMP-7 will be more general than disease specific. A second hypothesis to be tested is that replacement of BMP-7 in chronic kidney failure will maintain bone remodeling rates in the absence of secondary hyperparathyroidism. Recent data suggest that CKD is associated with a reduction in the osteoblast differentiation program such that in the absence of secondary hyperparathyroidism an adynamic bone disorder is observed. Studies in the application will demonstrate that BMP deficiency is a likely cause of the reduction in osteoblast differentiation produced by CKD.
The specific aims of the application are to analyze the therapeutic effectiveness of BMP-7 in animal models of CKD; to analyze the effect of BMP-7 in the treatment of renal osteodystrophy; and to analyze the mechanism of action of BMP-7 in inhibiting renal fibrogenesis. Protocols are proposed to demonstrate the therapeutic effectiveness of BMP-7 in the streptozotocin rat model of diabetic nephropathy and of cyclosporine-induced arteriolopathy and nephrosclerosis. A murine 5/6 nephrectomy model will be used to test the effectiveness of BMP-7 in restoring osteoblast differentiation in CKD associated with suppression of secondary hyperparathyroidism. Successful completion of the proposed studies will significantly clarify the usefulness of BMP-7 in CKD, and encourage its development as a new therapeutic agent.
