Research Project
2872260
The broad, long-term objective of this project is to determine if somatostatin (SS) analogues inhibit the excessive renal cell proliferation and fibrogemesis characteristic of many renal diseses. The current proposal addresses the hypothesis that SS and SS analogues 1) inhibit human proximal tubular epithelial cell (PTEC) and mesangial cell (MC) proliferation; and 2) decrease production of the extracellular matrix component, fibronectin (FN) and transforming growth factor-beta1 (TGF-beta1) after induction of these genes with the fibrogenic cytokines, angiotensin II (AII), growth hormone (GH), insulin-like growth factor-1 (IGF-1) or TFG-beta1. Preliminary studies from this laboratory support this hypothesis by demonstrating that 1) PTEC and MC express SS and several SS receptor (sst) subtypes, thus establishing a putative autocrine/paracrine pathway by which SS could modulate renal cell function; 2) SS inhibits PTEC proliferation in serum-free medium; and 3) exposure of tubular cells to SS inhibits FN and TGF-beta1 promoter activity. The specific aims and methods for this project are to: 1) Determine if SS inhibits PTEC and MC proliferation and FN and TGF-beta1 production by testing the effect of SS on proliferation, and on FN and TGF-beta1 expression with recombinant plasmid and adenovirus gene promoter constructs, Northern blot analysis and immunoassays after exposure of cells to AII, TGF-beta1, GH and IGF-1. 2) Determine which sst subtypes mediate inhibition of PTEC and MC proliferation and production of FN and TGF-beta1 by a) testing the ability of sst subtype- selective SS analogues to inhibit MC and PTEC proliferation and production of FN and TGF-beta1, and b) testing for sst subtype expression by Northern, immunoblot, and competitive binding analysis. Many chronic renal diseases, such as diabetic nephropathy, polycystic kidney disease and glomerulonephritis are characterized by fibrogenesis and/or excessive renal cell proliferation. If SS analogues prove to be efficacious in decreasing renal cell proliferation and expression of FN and TGF-beta1, the vast clinical experience with SS analogues that has accumulated for the treatment of other diseases can be exploited to design a novel, yet safe, adjunctive treatment to slow the progression of chronic renal disease.
