N-acetyl cysteine ameliorates ischemic renal failure.
Dimari, John, Judit Megyesi, Nora Udvarhelyi, Peter Price,roger Davis,
Robert Safirstein.
University of Texas Medical Branch at Galveston, 301 University
Blvd., 4.200 John Sealy Annex, Route #0562, Galveston, Texas 77555
-0562, (409) 772-1811 (phone), (409) 772-5451 (fax), Howard Hughes
Medical Institute, Program in Molecular Medicine, University of
Massachusetts Medical School, Worcester, MA 01605
APStracts 3:0205F, 1996.
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 cysteine (NAC), we determined whether
the Jun-N-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 BW)
infused 1h prior to and 1h 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 (GFR) at 1 day (0.9 +/- 0.2
(NAC) vs. 0.05 +/- 0.01 (C) ml/min, p<. 001) and 7 days (2.0
+/- 0.1 (NAC) vs 1.2 +/- 0.1 (C), p <.001) after the induction
of ischemia. NAC did not reduce the extent of proximal tubule
necrosis at 24 hours after reperfusion, but improved histologic
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.
Received 13 February 1996; accepted in final form 31 October
1996.
APS Manuscript Number F48-6.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 13 November 1996