N-acetyl cysteine ameliorates ischemic renal failure

Dimari, John F.; Megyesi, Judit; Udvarhelyi, Nóra; Price, Peter M.; Davis, Russell; Safirstein, Robert

doi:10.1152/ajprenal.1997.272.3.f292

Cited by 137 publications

(134 citation statements)

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“…SAPK activity is markedly increased in the proximal and distal tubules after IRI (110,178). Inhibition of SAPK activity during ischemia ameliorates renal failure (48). ERKs are another class of the MAPK family involved in mitogenic response and cellular differentiation.…”

Section: Protein Kinasesmentioning

confidence: 99%

Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis

Padanilam

2003

American Journal of Physiology-Renal Physiology

330

268

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In humans and experimental models of renal ischemia, tubular cells in various nephron segments undergo necrotic and/or apoptotic cell death. Various factors, including nucleotide depletion, electrolyte imbalance, reactive oxygen species, endonucleases, disruption of mitochondrial integrity, and activation of various components of the apoptotic machinery, have been implicated in renal cell vulnerability. Several approaches to limit the injury and augment the regeneration process, including nucleotide repletion, administration of growth factors, reactive oxygen species scavengers, and inhibition of inducers and executioners of cell death, proved to be effective in animal models. Nevertheless, an effective approach to limit or prevent ischemic renal injury in humans remains elusive, primarily because of an incomplete understanding of the mechanisms of cellular injury. Elucidation of cell death pathways in animal models in the setting of renal injury and extrapolation of the findings to humans will aid in the design of potential therapeutic strategies. This review evaluates our understanding of the molecular signaling events in apoptotic and necrotic cell death and the contribution of various molecular components of these pathways to renal injury.

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Section: Protein Kinasesmentioning

confidence: 99%

Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis

Padanilam

2003

American Journal of Physiology-Renal Physiology

330

268

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“…15,16 It also preserved renal function in animal models of ischemic kidney-injury. 17,18 N-acetylcysteine has already been studied extensively for preventing contrast-induced nephropathy. Despite initial promise, its efficacy in this setting has not been proven definitively.…”

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confidence: 99%

Recours à la N-acétylcystéine pour prévenir une atteinte rénale aiguë chez les patients de chirurgie cardiaque souffrant d’une insuffisance rénale modérée préexistante

Wijeysundera

Beattie

Rao

et al. 2007

Can J Anesth/J Can Anesth

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Purpose: N-acetylcysteine may prevent acute kidney injury after cardiac surgery. To determine if N-acetylcysteine warrants definitive evaluation in a large multicentre trial, we evaluated its effects on a surrogate outcome, estimated glomerular filtration rate (eGFR), in a randomized trial. Methods:One-hundred-seventy-seven cardiac surgery patients with moderate pre-existing renal insufficiency (eGFR ≤ 60 mL·min -1 ) were recruited in a blinded (patients, clinicians, datacollectors) placebo-controlled randomized trial. Eighty-nine were randomized to N-acetylcysteine (100 mg·kg -1 iv bolus, 20 mg·kg -1 ·hr -1 infusion until four hours after cardiopulmonary bypass), and 88 to placebo. The primary outcome was the percent change in eGFR during the first 72 postoperative hours. Secondary outcomes included renal replacement therapy, mortality, atrial fibrillation, vasoactive medications, and adverse effects. A future multicentre trial was deemed to be warranted if N-acetylcysteine was associated with a percent change in eGFR that was 3.8 better (small benefit), and with an upper 95% confidence interval including 9.5 (moderate benefit). Results: The median percent change in eGFR was 5.2% better (absolute difference) in the N-acetylcysteine arm (95% confidence interval 2.4% worse to 12.1% better; P = 0.22). With regard to secondary outcomes, all-cause mortality was lower in the N-acetylcysteine arm (0% vs 8%; P = 0.007). Conclusion:N-acetylcysteine did not cause a statistically significant improvement in postoperative eGFR in this singlecentre study. Nonetheless, its treatment effect was consistent with a plausible small-to-moderate benefit. Given this finding, N-acetylcysteine should be definitively evaluated in a large randomized trial.

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“…JNK and p38 have been implicated in the cellular stress signaling in the kidney after acute renal cell injury. Renal ischemia/reperfusion causes activation of JNK, p38, and ERK (4 -6), possibly as a direct consequence of oxidative stress (4,5). Also a variety of nephrotoxicants causes the activation of JNK and p38 (7)(8)(9).…”

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confidence: 99%

Heat Shock Protein 27 Is the Major Differentially Phosphorylated Protein Involved in Renal Epithelial Cellular Stress Response and Controls Focal Adhesion Organization and Apoptosis

Graauw

Tijdens

Cramer

et al. 2005

Journal of Biological Chemistry

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We used two-dimensional difference gel electrophoresis to determine early changes in the stress-response pathways that precede focal adhesion disorganization linked to the onset of apoptosis of renal epithelial cells. Treatment of LLC-PK1 cells with the model nephrotoxicant 1,2-(dichlorovinyl)-L-cysteine (DCVC) resulted in a >1.5-fold up-and down-regulation of 14 and 9 proteins, respectively, preceding the onset of apoptosis. Proteins included those involved in metabolism, i.e. aconitase and pyruvate dehydrogenase, and those related to stress responses and cytoskeletal reorganization, i.e. cofilin, Hsp27, and ␣-b-crystallin. The most prominent changes were found for Hsp27, which was related to a pI shift in association with an altered phosphorylation status of serine residue 82. Although both p38 and JNK were activated by DCVC, only inhibition of p38 with SB203580 reduced Hsp27 phosphorylation, which was associated with accelerated reorganization of focal adhesions, cell detachment, and apoptosis. In contrast, inhibition of JNK with SP600125 maintained cell adhesion as well as protection against apoptosis. Active JNK co-localized at focal adhesions after DCVC treatment in a FAK-dependent manner. Inhibition of active JNK localization at focal adhesions did not prevent DCVC-induced phosphorylation of Hsp27. Overexpression of a phosphorylationdefective mutant Hsp27 acted as a dominant negative and accelerated the DCVC-induced changes in the focal adhesions as well as the onset of apoptosis. Our data fit a model whereby early p38 activation results in a rapid phosphorylation of Hsp27, a requirement for proper maintenance of cell adhesion, thus suppressing renal epithelial cell apoptosis.

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N-acetyl cysteine ameliorates ischemic renal failure

Cited by 137 publications

References 0 publications

Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis

Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis

Recours à la N-acétylcystéine pour prévenir une atteinte rénale aiguë chez les patients de chirurgie cardiaque souffrant d’une insuffisance rénale modérée préexistante

Heat Shock Protein 27 Is the Major Differentially Phosphorylated Protein Involved in Renal Epithelial Cellular Stress Response and Controls Focal Adhesion Organization and Apoptosis

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