Attenuation of cisplatin-induced acute renal failure is associated with less apoptotic cell death.
To clarify the pathophysiologic role of apoptosis in acute renal failure (ARF), we examined whether the attenuation of cisplatin-induced ARF is associated with the change in the degree of apoptotic cell death. The administration of cisplatin (CDDP) (6 mg/kg body weight) in rats induced ARF at day 5, as manifested by a significant increase in serum creatinine (Scr) and tubular damage. CDDP-induced apoptotic cell death was confirmed by electron microscopic examination, agarose gel electrophoresis, and increased cells positive for TaT-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) in the outer medulla of the kidney. Treatment with dimethylthiourea (DMTU)--a scavenger of hydroxyl radicals--or glycine abrogated CDDP-induced increases in Scr, the tubular damage score, and the number of TUNEL-positive cells. Pretreatment with uranyl acetate (UA) induced a significant expression of Bcl-2 in the kidney and ameliorated CDDP-induced increases in Scr, the tubular damage score, and TUNEL-positive cells in the outer stripe of the outer medulla. Our findings indicate (1) that the attenuation of CDDP-induced ARF was associated with less apoptotic cell death and (2) that the induction of the anti-apoptotic protein Bcl-2 attenuated apoptosis and tubular damage. Our results suggest that apoptotic cell death may play an important role in the development of cisplatin-induced ARF.
Zhou
H
H
First Department of Medicine, Hamamatsu University School of Medicine, Japan.
Miyaji
T
T
Kato
A
A
Fujigaki
Y
Y
Sano
K
K
Hishida
A
A
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002945:Cisplatin / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D053938:DNA Fragmentation; D004587:Electrophoresis, Agar Gel; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D005998:Glycine / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use
D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; C005460:uranyl acetate; C038983:1,3-dimethylthiourea; D003404:Creatinine; D013890:Thiourea; D002945:Cisplatin; D005998:Glycine