Identification of cilostamide-responsive genes by differential display

Mesangial cell proliferation and recruitment of inflammatory cells are central features of many forms of glomerular injury. These processes are regulated by cytokine-raediated induction of several distinct signal transduction pathways. We have previously demonstrated that the cyclicAMP/phosphodiestcrase (PDE) system plays a critical role in these processes-synthetic PDE isoenzyme 3 specific inhibitors are potent inhibitors of cytokine-mediated mesangial cell proliferation (J. din. Invest. 96:401,1995). More recent studies have shown that cilostamide (CS, a PDE isoenzyme 3 specific inhibitor) blocks cytokine-stimulated mesangial cell expression of monocyte chemoattractant protein 1 (MCP-1) and that, in a rat model, PDE isoenzyme 3 inhibitors ameliorate acute glomerular injury induced by antithymocyte serum. Since CS may regulate a number of proinflammatory pathways, we have begun preliminary studies directed towards identification and characterization of genes regulated by CS. Differential display was performed on RNA isolated from mesangial cells treated with tumor necrosis factor (TNF), alone and in combination with CS; bands were subcloned and sequenced. Preliminary analysis has led to the identification of several differentially expressed genes related to the cell cycle, serine pretenses, and oxidative metabolism. Further characterization of these eene nroducts will lead to the identification of other inflammatDrv pathways regulated by CS.