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Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury

¹Chair of Nephrology, ²Department of Neuroscience, Unit of Physiology, ³Department of Clinical and Experimental Medicine, ⁴Department of Oral and Maxillofacial Sciences, ⁵Chair of Nephrology, University Magna Graecia of Catanzaro, and ⁶Department of Biology and Cellular and Molecular Pathology, University Federico II of Naples, Naples, Italy

Submitted 28 July 2005 ; accepted in final form 18 January 2006

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 signaling 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 phosphoinositide 3-kinase (PI3-kinase) signaling. Inhibition of Ras/ERK1/2 with a farnesyl transferase inhibitor, chaetomellic acid A (S-FTI), or with PD-98059, an inhibitor of MEK, a kinase upstream ERK1/2, significantly reduced the fraction of dead cells. The inhibitor of the PI3-kinase/Akt pathway, LY-294002, failed to exert a protective effect. We have translated these data in a rat model of renal ischemic injury in vivo. In uninephrectomized animals, anesthetized with pentobarbital sodium (Nembutal, 50 mg/kg ip), 24 h 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 [glomerular filtration rate (GFR) 0.17 ± 0.1 vs. 0.90 ± 0.4 ml·min^–1·100 g body wt^–1 in normal rats]. Rats treated with S-FTI maintained the renal function (GFR 0.50 ± 0.1 ml·min^–1·100 g body wt^–1), and the kidneys showed a significant 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 signaling significantly reduces acute postischemic renal injury.

signal transduction; kidney; endothelium; farnesyl transferase inhibitors

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