title: N-acetyl cysteine ameliorates ischemic renal failure.
abstract: Recovery from ischemic renal injury is accompanied by enhanced DNA synthesis and a typical immediate early (IE) gene response. These two processes occur in distinct cell populations, suggesting that the IE gene response does not serve a proliferative function directly. As cellular stress induces an IE response through activation of the stress-activated protein kinases (SAPK) that is not proliferative and can be inhibited by N-acetyl-L-cysteine (NAC), we determined whether the Jun NH2-terminal kinases (JNK), members of the SAPKs, are activated during ischemia and whether NAC administration reduces the IE response and/or the induction of JNK activity. NAC (6 mM/kg body wt) infused 1 h prior to and 1 h following renal ischemia reduced c-fos and c-jun expression by 50 and 70%, respectively. Ischemia increased JNK activity, and this increase was inhibited by NAC. NAC infused animals had a higher glomerular filtration rate at 1 day (NAC, 0.9 +/- 0.2, vs. control, 0.05 +/- 0.01 ml/min, P < 0.001) and 7 days (NAC, 2.0 +/- 0.1, vs. control, 1.2 +/- 0.1, P < 0.001) after the induction of ischemia. NAC did not reduce the extent of proximal tubule necrosis at 24 h after reperfusion but improved histological appearance of the kidney at 7 days. The mechanism by which NAC ameliorates the loss of renal function is unknown but may involve its general properties as an antioxidant or a possible interaction with NAC and NO. We conclude that the IE gene response of the kidney to ischemia reperfusion is a consequence of the stress-activated kinase pathway and that part of the response is deleterious to kidney function and cellular integrity.
authors.affiliation: University of Texas Medical Branch at Galveston, 77555-0562, USA.
authors.forename: J
authors.initials: J
authors.lastname: DiMari
authors.forename: J
authors.initials: J
authors.lastname: Megyesi
authors.forename: N
authors.initials: N
authors.lastname: Udvarhelyi
authors.forename: P
authors.initials: P
authors.lastname: Price
authors.forename: R
authors.initials: R
authors.lastname: Davis
authors.forename: R
authors.initials: R
authors.lastname: Safirstein
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009336:Necrosis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D015424:Reperfusion; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000111:Acetylcysteine