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Pathophysiology of Renal Disease and Progression |
BMediated Inflammation and on Tubular Cell Injury
Division of Nephrology, Department of Internal Medicine, Institute of Renal Disease, Korea University Hospital, Seoul, Korea
Address correspondence to: Dr. Won Yong Cho, Division of Nephrology, Department of Internal Medicine, Korea University Hospital, 126-1, 5Ka, Anam-Dong, Sungbuk-Ku, Seoul, Korea 136-705. Phone: +82-2-920-5599; Fax: +82-2-927-5344; E-mail: wonyong{at}korea.ac.kr
Received for publication October 18, 2005. Accepted for publication August 24, 2006.
Although heat preconditioning has been known to be protective in various types of injury, the precise molecular mechanism for this is unclear. Recent observations that indicate that previous heat shock has an anti-inflammatory, antiapoptotic effect led to this investigation of the in vivo effect of heat preconditioning on NF-
B activation and inflammation and also on tubular cell injury in ischemic acute renal failure (ARF). Heat preconditioning provided marked functional protection and also reduced histologic evidence of tubular necrosis. Ischemia/reperfusioninduced NF-
B activation was suppressed by heat preconditioning with a subsequent decrease in monocyte chemoattractant protein-1 expression and inflammatory cell infiltration. Heat preconditioning also suppressed the accumulation of phosphorylated inhibitory
B
(I
B
) with a resultant depletion of cytoplasmic I
B
, indicating that heat preconditioning blocked the activation of the I
B kinase complex. Tubular cell apoptosis, determined by terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling staining, also was decreased by heat preconditioning, and this was accompanied by decreased caspase 3 activation. Among several heat-shock proteins (HSP), HSP-70 was induced primarily by heat preconditioning. Inhibition of HSP-70 by quercetin almost completely reversed the functional protection that was provided by heat preconditioning. These data provide evidence that HSP-70 affords protection via inhibition of NF-
Bmediated inflammation and also inhibition of the cell death pathway in ischemic ARF. Further elucidation of the cytoprotective mechanism of stress proteins could facilitate new target or drug development in the treatment of ARF.
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