Acute renal failure in endotoxemia is dependent on caspase activation.
In previous work, it was demonstrated that apoptosis occurs in the kidney during LPS-induced acute renal failure (ARF). However, the relative importance of apoptosis in LPS-induced ARF remained unproven. Because the caspase enzyme cascade is responsible for carrying out apoptosis, it was hypothesized that treatment with a caspase inhibitor would protect mice from LPS-induced ARF. C57BL/6 mice received an injection of LPS and were treated with either the broad-spectrum caspase inhibitor z-VAD-fmk or vehicle and compared with unmanipulated mice. LPS induced a significant increase in caspase-3 activity in vehicle-treated mice, which was significantly inhibited by z-VAD. Mice that were treated with z-VAD were protected from ARF and demonstrated significantly less apoptosis as measured by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and DNA laddering. Although apoptosis is classically described as a noninflammatory process, z-VAD treatment significantly attenuated multiple markers of inflammation, such as renal neutrophil infiltration and renal expression of the neutrophil chemotactic factor macrophage inflammatory protein-2. Thus, caspase inhibition may protect against LPS-induced ARF not only by preventing apoptotic cell death but also by inhibiting inflammation. These data raise the possibility that apoptotic kidney cells may actually be a source of this local inflammation, contributing to subsequent nonapoptotic renal injury.
Guo
Rongqing
R
Section of Nephrology, University of Chicago, MC5100, Room S511, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Wang
Ying
Y
Minto
Andrew W
AW
Quigg
Richard J
RJ
Cunningham
Patrick N
PN
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019446:Endotoxemia / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D008070:Lipopolysaccharides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases