The fundamental mechanisms that mediate pathologic vascular and perivascular cellular proliferation in the kidney are not yet well defined. Such proliferation may cause vascular insufficiency through the lumenal narrowing seen in hypertensive nephrosclerosis, or it may result in the architectural disruption of functioning tissue units as in proliferative glomerulopathies. The goal of these studies is to identify the role of the vascular endothelial cell in producing mediators of vascular and perivascular proliferation. Cultured endothelial cells produce several well-characterized growth factors, including platelet-derived growth factor (PDGF) and interleukin 1 (IL-1), both of which affect the growth properties of cells that participate in pathologic subendothelial proliferation. The proposed work will address the in vitro and in vivo factors that influence endothelial expression of these growth factors and transforming growth factor beta (TGF-beta). We have recently shown the expression of PDGF activity by cultured human renal microvascular endothelial cells to be regulated by exposure of cells to thrombin and transforming growth factor beta (TGF-beta). We will quantify endothelial levels of specific growth factor messenger RNA and release of growth factor activity into conditioned medium as indices of in vitro growth factor expression under varying culture conditions and exposure to biochemical agonists relevant at sites of vascular proliferation. In vivo studies will use in situ hybridization methods to quantify growth factor mRNA expression levels in specific cell types (endothelium) within kidney specimens from patients with renal diseases marked by vascular and perivascular proliferation. Thus by combining in vitro and in vivo approaches, these studies should provide better understanding of the factors influencing renal endothelial growth factor expression and the role that local tissue growth factor production plays in renal vascular and perivascular proliferative diseases.
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