Published online before print January 23, 2003, doi: 10.1161/01.RES.0000057754.35180.99
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Submitted on June 4, 2002
Revised on January 14, 2003
Accepted on January 14, 2003
Liposomal Delivery of Heat Shock Protein 72 Into Renal Tubular Cells Blocks Nuclear Factor-
B Activation, Tumor Factor Necrosis-
Production, and Subsequent Ischemia-Induced Apoptosis
Kirstan K. Meldrum *;
From the Departments of Urology and Surgery (K.K.M., R.M., M.B.K.S., D.R.M.), Indiana University Medical Center, Indianapolis, Ind; Johns Hopkins Hospital (A.L.B., J.P.G.), Baltimore, Md; and the Department of Surgery (X.M.), University of Colorado Health Sciences Center, Denver, Colo.
* To whom correspondence should be addressed. E-mail: kkmeldrum{at}earthlink.net.
Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43°Cx1 hour) in renal tubular cells (LLC-PK1) with Western blot confirmation. Cells were subjected to simulated ischemia 24 hours after liposomal HSP72 transfer or thermal stress, and the effect of HSP72 on nuclear factor-
B (NF-B) activation (electrophoretic mobility shift assay and immunohistochemistry), IB
production (Western blot), postischemic tumor necrosis factor- (TNF-) production (RT-PCR), and apoptosis (TUNEL assay) were determined. In separate experiments, the role of TNF- in apoptosis was determined (anti-TNF- neutralizing antibody). Results demonstrated that both liposomal transfer of HSP72 and thermal induction of HSP72 prevented NF-B activation and translocation, TNF- gene transcription, and subsequent ischemia-induced renal tubular cell apoptosis. Furthermore, TNF- neutralization also inhibited ischemia-induced renal tubular cell apoptosis. These results indicate that liposomal delivery of HSP72 inhibits ischemia-induced renal tubular cell apoptosis by preventing NF-B activation and subsequent TNF- production. Further elucidation of the mechanisms of HSP-induced cytoprotection may result in therapeutic strategies that limit or prevent ischemia-induced renal damage.
Key words: inflammation • reperfusion • kidney
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