The Dimethylthiourea-Induced Attenuation of Cisplatin Nephrotoxicity Is Associated With the Augmented Induction of Heat Shock Proteins

Toxicol Appl Pharmacol. 2009 Jan 15;234(2):202-8. doi: 10.1016/j.taap.2008.09.031. Epub 2008 Oct 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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