application) This proposal will study the development of renal vasculature and the interactions between renal capillary endothelial cells and mesangial cells during development of the kidney. Diseases of the kidney which involve endothelial or mesangial cells have been well described. Because developmental pathways and response to injury share some common features, elucidation of the cellular and molecular mechanisms of renal organogenesis will not only increase understanding of developmental processes in the kidney, but may yield insights in to the pathogenic processes leading to renal disease. Although many of the fundamental stages in renal development have been described, the precise nature of the formation of vascular structures is not yet known, and it is not understood what is the origin of mesangial cells, or how they become localized to the glomerulus.
The specific aims of this proposal will therefore firstly examine what role transforming growth factor (TGF)-beta plays in capillary morphogenesis. Signaling through the type II TGF-beta receptor will be interrupted in embryonic rat kidney at day 13 of gestation (E13) by transducing explanted metanephric mesenchymes with a dominant negative mutant type II TGF-beta receptor (T-beta-R-IIM). The kidney will then be transplanted to the subcapsular region of syngeneic host and capillary morphogenesis assessed by light and electron microscopy. The results will be confirmed in vitro by culturing E13 kidneys in the presence or absence of exogenous TGF-beta. Secondly, T- beta-R-II positive stromal cells which associate with the vascular smooth muscle cell layer of developing vasculature may be progenitors of either mesangial cell or renin-producing cells in the juxtaglomerular apparatus. The origin of these cells will be determined with respect to whether they arise from within the kidney, or whether they migrate into the kidney from without by transplantation of adenovirus/lac Z transduced E13 kidneys into adults. Lastly, the regulation of endothelial platelet-derived growth factor (PDGF)-B by endothelial TGF-beta and the role endothelial PDGF-B plays in the survival and/or proliferation of mesangial cells, and their ultimate localization to the glomerulus will be studied. E13 kidneys will be transduced with T-beta-R-IIM under the control of an endothelial cell- specific promoter and effects on endothelial cell PDGF-B assessed. By immunohistochemistry and electron microscopy, effects of diminished endothelial PDGF-B on mesangial cells will be determined.
| Eng, Eudora; Holgren, Cory; Hubchak, Susan et al. (2005) Hypoxia regulates PDGF-B interactions between glomerular capillary endothelial and mesangial cells. Kidney Int 68:695-703 |
| Eng, Eudora; Ballermann, Barbara J (2003) Diminished NF-kappaB activation and PDGF-B expression in glomerular endothelial cells subjected to chronic shear stress. Microvasc Res 65:137-44 |
| Neumeister, Peter; Albanese, Chris; Balent, Beate et al. (2002) Senescence and epigenetic dysregulation in cancer. Int J Biochem Cell Biol 34:1475-90 |
