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The role of Bax in carvedilol protection against cisplatin nephrotoxicity

2012; Elsevier BV; Volume: 211; Linguagem: Inglês

10.1016/j.toxlet.2012.03.422

1879-3169

Maria Augusta Carvalho Rodrigues, Marcia Cristina Faria Faria, Neife Apaecida Guinaim do Santos, Glenda C. Gobé, Antônio C. Santos,

Nanoparticle-Based Drug Delivery

Purpose: Cisplatin (CIS) is a highly effective, but nephrotoxic chemotherapeutic drug. We have already reported the protective effect of the antihypertensive carvedilol (CV), known to be antioxidant, against cisplatin-induced renal mitochondrial toxicity. Here we show the inhibitory effect of carvedilol on the pro-apoptotic protein Bax.Methods: Adult Swiss mice bearing sarcoma-180 tumors in their right hind legs were divided into four groups (n = 8): control (C, saline and 0.5% carboximethylcelulose); CIS (25 mg/kg i.p., day 1); CV (10 mg/kg, gavage, days 1–3); CV + CIS (CV 10 mg/kg, days 1–3 and CIS 25 mg/kg, day 1). After 72 h, animals were euthanized, kidneys were collected, fixed in formalin and embebed in paraffin. Kidney sections (4 μm) were submitted to hematoxylin/eosin staining and immunohistochemistry for Bax, Bcl-xL and caspase-3. Apoptosis was also evaluated in situ (ApopTag® Millipore). Labeled areas were determined using Aperio ImageScope software (San Diego, CA, USA). Statistics: Mann–Whitney (p < 0.05). Results and conclusions: CIS presented significantly increased (i) renal tubular lesion (70.47 ± 1.68%); (ii) Bax (15,171.10 ± 3179.00 positive pixel count (ppc)); (iii) caspase-3 (40,642.50 ± 3677.67 ppc); and (iv) apoptosis (62,347.40 ± 10,014.00 ppc) as compared to C (0.41 ± 0.16%, 616.55 ± 157.10, 546.12 ± 173.97, and 388.89 ± 74.35 ppc, respectively). CV + CIS presented significantly lower results (11.90 ± 3.50%; 5419.35 ± 1436.00 ppc; 8515.75 ± 4050.85 and 4661.95 ± 1879.00 ppc, respectively) as compared to CIS. There was no significant difference in the anti-apoptotic protein Bcl-xL. No significant difference was observed between C and CV for any parameter. Results show that inhibition of the pro-apoptotic protein Bax is involved in the protective action of carvedilol against cisplatin nephrotoxicity.