The small GTPase p21 Ras and its downstream effectors play a central role in the control of cell survival and apoptosis. We studied the effects of Ras/ERK1/2 signalling inhibition on oxidative damage in cultured renal and endothelial cells and on renal ischemia-reperfusion injury in the rat. Primary human renal tubular and human endothelial ECV304 cells underwent significant cell death when subjected to oxidative stress. This type of stress induced robustly ERK1/2 and PI3 kinase signalling. Inhibition of Ras/ERK1/2 with a farnesyl transferase inhibitor, chaetomellic acid A (S-FTI) or with PD98059, an inhibitor of MEK, a kinase upstream ERK1/2, significantly reduced the fraction of dead cells. The inhibitor of PI3Kinase/Akt pathway, LY294002, failed to exert a protective effect. We have translated these data in a rat model of renal ischemic injury in vivo . In uni-nephrectomized animals, anaesthetized with sodium pentobarbital (Nembutal, 50 mg/kg i.p.), 24 hours after an acute ischemic renal insult (45 min occlusion of left renal artery) a significant fraction of kidney cells succumbed to cell death resulting in renal failure (GFR 0.17±0.1 vs 0.90±0.4 ml/min/100 g b.w. in normal rats). Rats treated with S-FTI, main-tained the renal function (GFR 0.50±0.1 ml/min/100 g b.w.) and the kidneys showed a sig-nificant reduction of tubular necrosis. Reduction of ischemic damage in kidney and tubular cells paralleled Ha-Ras inhibition, assayed by cytosolic translocation of the protein. These data demonstrate that inhibition of farnesylation and consequently of Ras/ERK1/2 signalling significantly reduces acute post-ischemic renal injury. These data demonstrate that inhibition of farnesylation and consequently of Ras/ERK1/2 signalling significantly reduces acute post-ischemic renal injury.