Ras Antagonist Farnesylthiosalicylic Acid (FTS) Reduces Glomerular Cellular Proliferation and Macrophage Number in Rat Thy-1 Nephritis

Targeting the Ras family of monomeric GTPases has been suggested as a therapeutic strategy in proliferative renal diseases. This article reports the effects of Ras antagonist farnesylthiosalicylic acid (FTS) in rat thy-1 nephritis, a model in which cytokine-driven glomerular cell proliferation and invasion is likely to involve Ras signaling pathways. FTS in vitro specifically inhibits the binding of Ras to discrete membrane sites, thereby downregulating several Ras-dependent signaling functions and accelerating Ras degradation. Forty-four Lewis rats were given nephritis by day zero injection of a monoclonal thy-1 antibody ER4 (2.5mg/kg body wt). Twenty-two rats were then treated with daily intraperitoneal injection of FTS (5 mg/kg body wt) until sacrifice, and the remaining control rats were given vehicle alone (C). Six rats from each group were sacrificed at day 1 to establish equal injury; other sacrifice points were day 7 and day 10. Bromo-deoxyuridine (BrdU) was injected 1 h before sacrifice, after which sections were used for immunohistochemistry, which included detection of Ras expression, BrdU+ cells and macrophages/monocytes (ED1+). Thy-1 nephritis was associated with an increase in glomerular expression of Ki-Ras and N-Ras isoforms, which was almost fully prevented by FTS. FTS treatment was associated with: (a) a 54% reduction in the mean number of BrdU+ cells per glomerulus (P < 0.01), (b) a 50% reduction in macrophages/monocytes (ED1+) per glomerulus (P < 0.01), and (c) a reduction in 24-h proteinuria at day 10 (P < 0.05). These results show that Ras inhibition can reduce both glomerular cell proliferation and glomerular macrophage cell number in the thy-1 model and justify further study of FTS as a potential therapeutic in proliferative nephritis.