The dimethylthiourea-induced attenuation of cisplatin nephrotoxicity is associated with the augmented induction of heat shock proteins.

Abstract

Dimethylthiourea (DMTU), a potent hydroxyl radical scavenger, affords protection against cisplatin (CDDP)-induced acute renal failure (ARF). Since the suppression of oxidative stress and the enhancement of heat shock proteins (HSPs) are both reported to protect against CDDP-induced renal damage, we tested whether increased HSP expression is involved in the underlying mechanisms of the DMTU-induced renal protection. We examined the effect of DMTU treatment on the expression of HSPs in the kidney until day 5 following a single injection of CDDP (5 mg/kg BW). DMTU significantly inhibited the CDDP-induced increments of serum creatinine, the number of 8-hydroxyl-2'-deoxyguanosine (8-OHdG)- and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL)-positive tubular cells, and tubular damage score (p<0.05). CDDP significantly increased renal abundances of HO-1, HSP60, HSP72 and HSP90 at days 1, 3, and 5. DMTU significantly augmented only the expression of HSP60 expression mainly in the cytoplasm of the proximal tubular cells at days 1 and 3 in CDDP-induced ARF. DMTU also inhibited the CDDP-induced increment of Bax, a pro-apoptotic protein, in the fraction of organelles/membranes at day 3. The findings suggest that DMTU may afford protection against CDDP-induced ARF, partially through the early induction of cytoplasmic HSP60, thereby preventing the Bax-mediated apoptosis in renal tubular cells.

• Authors: Takayuki Tsuji, Akihiko Kato, Hideo Yasuda, Takehiko Miyaji, Jinghui Luo, Yukitoshi Sakao, Hideaki Ito, Yoshihide Fujigaki, Akira Hishida
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 234 Issue 2 Pg. 202-8 (Jan 15 2009) ISSN: 1096-0333 [Electronic] United States
• PMID: 18992762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Heat-Shock Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• 1,3-dimethylthiourea
• Heme Oxygenase-1
• Thiourea
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, metabolism, prevention & control)
• Animals
• Antineoplastic Agents (antagonists & inhibitors, toxicity)
• Blotting, Western
• Cisplatin (antagonists & inhibitors, toxicity)
• Heat-Shock Proteins (biosynthesis)
• Heme Oxygenase-1 (metabolism)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Kidney (drug effects, metabolism)
• Male
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Thiourea (analogs & derivatives, pharmacology)
• bcl-2-Associated X Protein (biosynthesis, genetics)