Role of endothelin-1 antagonist; bosentan, against cisplatin-induced nephrotoxicity in male and female rats

Abstract

Background: Cisplatin (CP) is a chemotherapy drug, with the major side effect of nephrotoxicity. The level of endothelin-1 (ET-1) increases during nephrotoxicity, which is accompanied with vasoconstrictive properties. Bosentan (BOS) is a nonselective ET-1 receptor antagonist, having vasodilatory and anti-hypertension effects. The purpose of this study was to investigate the renoprotective effect of BOS against CP-induced nephrotoxicity in male and female rats.

Materials and methods: Male and female rats were divided into six groups; groups 1-3 and 4-6 were male and female rats, respectively. Animals in groups 1 and 4 were considered as negative control and groups 2 and 5 considered as positive control groups received BOS (30 mg/kg/day) alone and CP (2.5 mg/kg/day) alone, respectively, for 1-week. The animals in groups 3 and 6 were treated with both CP and BOS. Finally, serum parameters were measured, and the kidney tissue was subjected to staining to evaluate tissue damage.

Results: The serum levels of blood urea nitrogen and creatinine, kidney tissue damage score and kidney weight elevated, and body weight significantly decreased in both CP alone and in CP plus BOS-treated groups when compared with the control groups (P < 0.05), while BOS did not ameliorate these parameters neither in males nor in females. No significant differences were observed in serum levels of nitrite and malondialdehyde between the groups, but kidney tissue level of nitrite decreased significantly in CP alone and CP plus BOS-treated groups (P < 0.05).

Conclusion: Renoprotective effect of BOS, as ET-1 blocker, was not observed against CP-induced nephrotoxicity neither in male nor in female rats. This is while BOS promoted the severity of injuries in females.

Keywords: Bosentan; cisplatin; gender; nephrotoxicity; rat.

Figure 1

Comparison of the sham (treated with bosentan [BOS] alone), positive control (treated with cisplatin [CP] alone), and case (treated with BOS plus CP) groups in each gender with regard to the measured BUN, creatinine, kidney weight, bodyweight change, kidney tissue damage score, and kidney nitrite. Data are reported as mean ± standard error of mean *indicates significant difference from the sham group and #indicates significant difference from the positive control group, and -indicates significant difference between the case groups in the two genders. BUN: Blood urea nitrogen, Cr: Creatinine, KW: Kidney weight/100 g bodyweight, BW: Bodyweight change, KTDS: Kidney tissue damage score, KN: Kidney nitrite, BOS: Bosentan, and CP: Cisplatin

Figure 2

Sample image from kidney tissue of all experimental groups