Evaluation of renal protective effects of inhibiting TGF-β type I receptor in a cisplatin-induced nephrotoxicity model

Eur Cytokine Netw. Oct-Dec 2013;24(4):139-47. doi: 10.1684/ecn.2014.0344.

Abstract

Purpose: The use of cisplatin, the first of the platinum-containing anti-cancer drugs, is limited by the development of a myriad of adverse reactions, including nephrotoxicity. We conducted this study therefore to find out whether SB-431542, potent and specific inhibitor of type I transforming growth factor-beta receptor (TGF-βR1), could prevent or attenuate kidney damage in rats, and to elucidate its possible mechanism of action.

Methods: Fifty rats were treated with cisplatin (10 mg/kg) in the presence (1 and 3 mg/kg) or absence of SB-431542. Morphological changes were assessed in kidney sections stained with H/E. Oxidative stress was evaluated in kidney homogenates by measuring malondialdehyde (MDA) and superoxide dismutase (SOD). Kidney samples were used for measurements of TGF-βR1, TGF-β1 and sCD93 by ELISA. Kidney tissue apoptosis was assessed by measuring caspase-3 activity.

Results: The renal protective effect of SB-431542 was confirmed by the normal appearance of renal tissue and the relatively unaffected serum creatinine and urea levels. With SB-431542, there was significantly lower renal MDA and increased SOD compared with the cisplatin group. Furthermore, in the SB-431542 group, renal TGF-βR1, TGF-β1, sCD93 and caspase-3 levels were significantly lower.

Conclusions: Inhibition of TGF-βR1 provides protective effects against cisplatin-induced nephrotoxicity through several mechanisms, including attenuation of oxidative stress, inhibition of pro-inflammatory cytokines, blocking of renal fibrosis markers, and anti-apoptotic effects.

Keywords: MDA; SB-431542; SOD; TGF-β1; TGF-βR1; caspase-3; cisplatin; sCD93.

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Benzamides / pharmacology
  • Caspase 3 / analysis
  • Cisplatin / toxicity*
  • Dioxoles / pharmacology
  • Kidney / pathology
  • Kidney Diseases / chemically induced
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / prevention & control
  • Male
  • Malondialdehyde / analysis
  • Membrane Glycoproteins / analysis
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Complement / analysis
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Superoxide Dismutase / analysis
  • Transforming Growth Factor beta1 / analysis

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Antineoplastic Agents
  • Benzamides
  • Dioxoles
  • Membrane Glycoproteins
  • Receptors, Complement
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • complement 1q receptor
  • Malondialdehyde
  • Superoxide Dismutase
  • Caspase 3
  • Cisplatin