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

2006; American Physical Society; Volume: 290; Issue: 6 Linguagem: Inglês

10.1152/ajprenal.00304.2005

1931-857X

Massimo Sabbatini, Mariarosaria Santillo, Antonio Pisani, Roberto Paternò, F. Uccello, Rosalba Serù, Gianfranco Matrone, Gianrico Spagnuolo, Michele Andreucci, Vittorio Serio, Pasquale Esposito, Bruno Cianciaruso, Giorgio Fuíano, Enrico V. Avvedimento,

Trace Elements in Health

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.