Abstract
Using morphological and molecular approaches, we characterized cisplatin-induced cell necrosis and apoptosis in rat kidney. Male Sprague-Dawley rats (n=5 per group) received a single intraperitoneal injection of either cisplatin (5 mg/kg) or saline, and were killed on day 5. Functionally, cisplatin-treated rats developed polyuric acute renal failure. Morphologically, kidneys of cisplatin-treated rats showed overt tubular necrosis associated with apoptosis in the corticomedullary junction. Cell necrosis was segment-specific and was distributed in radial fashion at the corticomedullary junction. The apoptosis was limited to discrete cells in apparently intact tubules in the vicinity of the necrosed tubules. The apoptotic changes were confirmed by TUNEL (TdT-mediated deoxyuridine triphosphate nick-end labeling) and staining for cleaved caspase-3. Analysis of outer medullary tissue for apoptosis-related molecules by RNase protection assay revealed a significant increase in the expression of pro-apoptotic mRNAs (caspases 1, 2, and 8, and Bax) in cisplatin-treated rats. On the other hand, the expression of mRNA for the anti-apoptotic Bcl-2 did not change, resulting in a decrease in relative ratio of Bcl-2/Bax, and thus favoring apoptosis. The above changes were paralleled by a marked increase in caspase-3 precursor, the executioner protease. Furthermore, these pro-apoptotic molecular changes were associated with a 3-fold increase in the activity of JNK1 in the outer medulla, but not in the cortex, of cisplatin-treated rat kidneys, localizing to the site of maximal apoptosis. Upregulation of JNK1 activity in the outer medulla was not accompanied by changes in the activities of ERK or p38 kinase. In conclusion, these data suggest that cisplatin-induced apoptotic cell death in native kidney may be mediated by cooperative activation of the JNK1 pathway and Bax in the outer medulla.
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Acknowledgement
This work was supported by funds from the US National Institutes of Health (R01 DK-53452 to ARB), the University of Cincinnati, Cincinnati, Ohio (WC), Dialysis Clinic Incorporated, Cincinnati, Ohio (BKK), and the University of Utah Health Sciences Center, Salt Lake City, Utah (BKK). This material is the result of work supported in part with resources and the use of facilities at the Veterans Administration Salt Lake City Health Care System, Salt Lake City, Utah (BKK). The authors thank Darren DiIulio, Nithya Krishnan, and Yu Yang for their technical assistance, and Drs. Christof Westenfelder and Donald Kohan for critically reading the manuscript.
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Sheikh-Hamad, D., Cacini, W., Buckley, A.R. et al. Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. Arch Toxicol 78, 147–155 (2004). https://doi.org/10.1007/s00204-003-0521-4
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DOI: https://doi.org/10.1007/s00204-003-0521-4