Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis.
BACKGROUND
Cisplatin is a commonly used chemotherapeutic agent which causes apoptosis or necrosis of renal tubular epithelial cells in vitro. Caspases are a family of cysteine proteases that mediate apoptosis (caspase-3) and inflammation (caspase-1). Although well studied in vitro, caspases have not been previously studied in cisplatin-induced acute renal failure (ARF) in vivo.


METHODS
Cisplatin (30 mg/kg) was injected intraperitoneally into wild-type and caspase-1-deficient (-/-) C57BL/6 mice. Serum creatinine and blood urea nitrogen (BUN), and renal caspase-1, -3, -8 and -9 activity were measured on days 1, 2, and 3 after cisplatin injection. Kidneys were examined for acute tubular necrosis (ATN), neutrophils, and apoptosis on days 1, 2, and 3.


RESULTS
After cisplatin injection, serum creatinine and BUN were normal on day 1, began to increase on day 2, and peaked on day 3. Similarly, ATN scores and neutrophil counts peaked on day 3. In contrast, renal apoptosis significantly increased on day 2. Renal dysfunction, apoptosis, ATN scores and neutrophil infiltration were all reduced in the caspase-1(-/-) mice. In wild-type mice, caspase-1 and -3 activity increased on days 2 and 3. Caspase-3 activity was reduced by approximately 50% in caspase-1(-/-) mice; active caspase-3 detected by immunoblot was also reduced in caspase-1(-/-) mice. In vitro, addition of recombinant caspases to kidney cytosolic extracts determined that caspase-1 activates caspase-3 in renal tissue.


CONCLUSIONS
These results indicate that caspase-1 contributes to cisplatin-induced ARF and ATN (day 3). Furthermore, caspase-1 affects caspase-3 activation and apoptosis in cisplatin-induced ARF (day 2).
Faubel
Sarah
S
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Ljubanovic
Danica
D
Reznikov
Leonid
L
Somerset
Hilary
H
Dinarello
Charles A
CA
Edelstein
Charles L
CL
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000502:physiology; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D003600:Cytosol / Q000201:enzymology; D015151:Immunoblotting; D007668:Kidney / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009336:Necrosis; D009504:Neutrophils / Q000473:pathology
D000970:Antineoplastic Agents; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1; D002945:Cisplatin