Cell Biology – Immunology – Pathology

Kidney International (2004) 66, 2202–2213; doi:10.1111/j.1523-1755.2004.66010.x

Caspase-1–deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis

SARAH FAUBEL, DANICA LJUBANOVIC, LEONID REZNIKOV, HILARY SOMERSET, CHARLES A DINARELLO and CHARLES L EDELSTEIN

Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and Department of Pathology, University Hospital Dubrava, Zagreb, Croatia

Correspondence: Charles L Edelstein, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Box C281, 4200 E. 9th Ave, Denver, CO 80262. E-mail:charles.edelstein@uchsc.edu

Received 29 October 2003; Revised 7 April 2004; Re-revised 1 June 2004; Accepted 22 June 2004.

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Abstract

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.

Conclusion

 

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).

Keywords:

cisplatin-induced ARF, caspase-1, caspases, apoptosis, necrosis, inflammation

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