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

Abstract

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 i.p.), 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 x min(-1) x 100 g body wt(-1) in normal rats]. Rats treated with S-FTI maintained the renal function (GFR 0.50 +/- 0.1 ml x min(-1) x 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.

The potential use of biomarkers in predicting contrast-induced acute kidney injury

“…[165][166][167][168] Serum and urine levels of miR-21 also predicted the progression of AKI in cardiac surgery patients. 169 In an in vivo mouse model study, renal ischemia reperfusion caused the increase of several miRNA molecules in plasma and kidneys when compared with sham-treated mice, at 3 hours, 6 hours and 24 hours following the ischemic injury.…”

Targeted Genomic Disruption of H-Ras Induces Hypotension Through a NO-cGMP-PKG Pathway–Dependent Mechanism

“…23 Blood pressure was measured under basal conditions and after the administration of the following treatments: acetylcholine (ACh) (1 g/kg body weight [BW] intraperitoneal [IP]), sodium nitroprusside (SNP) (2 g/kg BW IP), db-cGMP (5 mg/kg BW IP), N G -nitro-L-arginine methyl ester (L-NAME) (20 mg/kg BW per day, drinking water for 2 weeks), 1H- [1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ) (5 mmol/kg BW IP), DT-3 (500 g/kg BW IP), and chaetomellic acid A (1.5 mg/kg BW IP at 24 and 16 hours before blood pressure measurement and euthanasia). 24 …”

Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

“…ERK1/2 is also activated by cell stressors, including reactive oxygen species. In a study utilizing H 2 O 2 injury in human renal cells, ERK1/2 inhibition was shown to decrease necrosis and apoptosis (5), whereas in a cisplatin-induced cell injury model, ERK1/2 inhibition reduced caspase 3 activation and apoptosis (6). In renal proximal tubular cells (RPTC), phosphorylated ERK1/2 was shown to reduce mitochondrial respiration and ATP production by decreasing complex I electron transport chain activity in response to tert-butyl hydroperoxide (TBHP), a model oxidant (7).…”