It is estimated that by 2010, the annual increase in end-stage renal disease (ESRD) will exceed 170,000 cases with a prevalence of over 660,000 patients. It is further estimated that the yearly cost of treating patients with ESRD will be over 39 billion in pre-Katrina dollars. By most accounts, changes in the microscopic appearances in the interstitium of the kidney correlate with the decline of renal function leading to ESRD. A part of the renal interstitium that has been minimally investigated are the endothelial cells of the peritubular capillaries. Bone Morphogenetic Protein-7 (BMP-7) has renoprotective and renoregenarative properties blunting progression of ESRD. The general hypothesis being tested is that part of the renoprotective and renorestorative effects of BMP-7 are due to this growth factor being endothelial-protective and endothelial restorative. It is postulated that BMP-7 directly effects renal endothelial cells and promotes angiogenesis in the 3-dimensional extracellular matrix of the kidneys. {By developing strategies to preserve/restore renal peritubular capillaries; this project may contribute to prolonging renal function thereby minimizing the costs associated with treating ESRD}.
The specific aims of this proposal are to; 1) Determine the effects of exogenous BMP-7 on endothelial cell biology in vitro; and 2) Determine the effects of exogenous BMP-7 on renal endothelial cell biology in vivo. These experiments will utilize an immortalized mouse endothelial cell line in both 2-dimentional and 3- dimensional cell culture with collagen 1 and collagen IV matrices. The cells in culture will be treated or not with BMP-7 and/or transforming growth factor-beta (TGF-?) and assessed for migration, proliferation, apoptosis and capillary tube formation. The contribution of various protein kinase pathways and blockade of the kinases on these processes will be determined. The in vivo studies will utilize a reproducible animal model of renal fibrosis the mouse with acute and chronic unilateral ureteral obstruction (UUO). {The findings relevant to peritubular capillary integrity in the UUO model will be further tested in an obese mouse model that develops hyperglycemia. The obese model will have broader implications to chronic kidney disease while the acute UUO model will identify mechanisms by which BMP-7 is endothelial protective}. Dual-label immunocytochemistry will be employed to identify renal endothelial cells and the impact of BMP-7 treatment along with TGF-? modulation on protein kinase activities within and adjacent to the endothelial cells. The in vitro and in vivo studies will be integrated to maximize the effects of BMP-7 treatment that preserve renal endothelial cells and in turn, renal epithelial cells and ultimately renal function. If a Medicare patient with kidney disease does not progress to dialysis the estimated savings to Medicare is $250.000 for each patient. This proposal examines a treatment designed to delay or halt the progression of renal disease thereby saving a significant portion of the yearly Medicare budget. ? ? ?
