Evidence against protective role of sex hormone estrogen in Cisplatin-induced nephrotoxicity in ovarectomized rat model

Abstract

Background: Cisplatin (CP) is an effective drug in cancer therapy to treat the solid tumors, but it is accompanied with nephrotoxicity. The protective effect of estrogen in cardiovascular diseases is well-documented; but its nephron-protective effect against CP-induced nephrotoxicity is not completely understood.

Materials and methods: Thirty ovarectomized Wistar rats were divided in to five groups. Groups 1-3 received different doses of estradiol valerate (0.5, 2.5 and 10 mg/kg/week) in sesame oil for 4 weeks, and at the end of week 3, a single dose of CP (7 mg/kg, intraperitoneal [IP]) was administrated. Group 4 (positive control) received the same regimen as group 1-3 without estradiol without vehicle. The negative control group (Group 5) received sesame oil during the study. The animals were sacrificed 1 week after CP injection for histopathological studies.

Results: The serum level of blood urea nitrogen and creatinine, kidney tissue damage score (KTDS), kidney weight and percentage of body weight change in CP-treated groups significantly increased (P < 0.05), however, there were no significant differences detected between the estrogen-treated groups (Groups 1-3) and the positive control group (Group 4). Although, estradiol administration enhanced the serum level of nitrite, it was not affected by CP. Finally, significant correlation between KTDS and kidney weight was detected (r (2) = 0.63, P < 0.01).

Conclusion: Estrogen is not nephron-protective against CP-induced nephrotoxicity. Moreover, it seems that the mechanism may be related to estrogen-induced oxidative stress in the kidney, which may promote the nephrotoxicity.

Keywords: Cisplatin; estrogen; nephrotoxicity; ovarectomized rat.

Figure 1

Serum level of blood urea nitrogen (BUN), creatinine (Cr) and nitrite. The star (^*) and (†) indicate significant difference (P < 0.05) when compared with the negative and the positive control groups, respectively. For the serum levels of BUN and Cr, no significant differences were detected between Groups 1 and 4

Figure 2

The percentage (%) of change weight, total kidney weight/100 gr body weight, and the kidney tissue damage score. The star (^*) indicates significant difference (P < 0.05) when compared with negative control group. For the above parameters, no significant differences were detected among Groups 1-4

Figure 3

Images (magnification ×100) of kidney tissue. (a) Group 1; low- dose of estradiol + cisplatin, (b) Group 2; mid dose of estradiol + cisplatin, (c) Group 3; high- dose of estradiol + cisplatin, (d) Group 4; vehicle + cisplatin, (e) Group 5; sesame oil. Higher tissue damage was observed in estrogen-treated and positive control groups