title: Evaluation of renal protective effects of inhibiting TGF-β type I receptor in a cisplatin-induced nephrotoxicity model.
abstract: OBJECTIVE
  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.
authors.affiliation: Dept. of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
authors.forename: Hala S
authors.initials: HS
authors.lastname: Bayomi
authors.affiliation: Dept. of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
authors.forename: Nehal M
authors.initials: NM
authors.lastname: Elsherbiny
authors.affiliation: Dept. of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
authors.forename: Amal M
authors.initials: AM
authors.lastname: El-Gayar
authors.affiliation: Dept. of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
authors.forename: Mohammed M H
authors.initials: MM
authors.lastname: Al-Gayyar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D053148:Caspase 3 / Q000032:analysis; D002945:Cisplatin / Q000633:toxicity*; D004149:Dioxoles / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011951:Receptors, Complement / Q000032:analysis; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013482:Superoxide Dismutase / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000032:analysis
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004149:Dioxoles; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C032402:complement 1q receptor; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D053148:Caspase 3; D002945:Cisplatin
keywords: MDA; SB-431542; SOD; TGF-β1; TGF-βR1; caspase-3; cisplatin; sCD93