Nephroprotective effect of estrogen and progesterone combination on cisplatin-induced nephrotoxicity in ovariectomized female rats

Abstract

Recently, we reported that estrogen (Es) has no beneficial effect on cisplatin (CP)-induced nephrotoxicity, but the role of progesterone (Pr) and the combination of Es and Pr are not yet well-defined. In this study, we investigated the protective role of Pr, and co-administration of Es/Pr on CP-induced nephrotoxicity. Eighty-six ovariectomized female Wistar rats were divided into 13 groups, and the experiments were performed in two phases. In Phase I, Groups 1-4 received 2, 5, 10, and 25 mg/kg, IM Pr dissolved in sesame oil every 5 days for four doses. Groups 5-8 had the same treatment regimen as Groups 1-4, but after the third injection the animals also received continuous dose of CP (2.5 mg/kg/day, i.p.) for 8 days. Group 9, as the positive control group, received sesame oil instead of Pr plus CP. Group 10, as the negative control group, received sesame oil instead of Pr. After the most effective dose of Pr was determined in Phase I, Groups 11-13 in Phase II received 10 mg/kg Pr plus either 0.25, 0.5, or 1 mg/kg, IM estradiol valerate every 5 days for four doses. After the third injection, they also received a continuous dose of CP for 8 days. The levels of blood urea nitrogen (BUN) and creatinine (Cr), kidney tissue damage score (KTDS), and kidney weight (KW) increased and body weight (BW) decreased in the positive control group (P < 0.05). Administration of Pr (10 mg/kg) plus CP decreased KTDS and BW loss and KW. Co-administration of ES/Pr at specific doses improved Cr, BUN, and KTDS; and resulted in reduced CP-induced nephrotoxicity. The results obtained suggest that the beneficial effect of Pr on CP-induced nephrotoxicity is dose-dependent. In addition, combination of Es/Pr with a specific dose decreased CP-induced nephrotoxicity.

Keywords: Cisplatin; estrogen; nephrotoxicity; progesterone; rats.

Diagram 1

The experimental design of the study. Phase I: Groups 5–8 received 2, 5, 10, and 25 mg/kg, progesterone (Pr) every 5 days during the study (total of 4 doses), while after the third injection of Pr the animals also received continuous dose of cisplatin (CP, 2.5 mg/kg/day) for 8 days. Groups 1–4 had the same treatment regimen as Groups 5–8, but saline instead of CP. Group 9, as the positive control group, received sesame oil instead of Pr plus CP. Group 10, as the negative control group, received sesame oil instead of Pr plus saline instead of CP. Phase II: Groups 11–13 in phase II received 10 mg/kg Pr plus either 0.25, 0.5, or 1 mg/kg, im estradiol valerate (Es) every 5 days (total of 4 doses) while after the third injection, they also received continuous dose of CP for 8 days (e)

Figure 1

Serum blood urea nitrogen (BUN) and creatinine, kidney tissue damage score, total kidney weight and weight change (delta weight) in all experimental groups (Phase 1). (a) The effect of progesterone on CP-induced nephrotoxicity. (b) The effect of progesterone (Pr) on the parameters measured. *, and, ×, §, and #indicate significant difference (P < 0.05) from the positive control (CP), Pr 2 + CP, Pr 5 + CP, Pr 10 + CP, and Pr 25 + CP, respectively

Figure 2

Serum blood urea nitrogen and creatinine, kidney tissue damage score, total kidney weight, and delta weight in all experimental groups (Phase 2). The effect of co-administration Es/Pr on CP-induced nephrotoxicity. *, †, and o indicate significant difference from positive control (CP), Pr 10, and Pr 10+CP groups, respectively

Figure 3

Kidney tissue images (×100) in all the experimental groups. kidney tissue damage score was based on hyaline cast, debris, vacuolization, flattening and degeneration of tubular cells, and dilatation of tubular lumen and graded from 0 to 4. Groups 9 and 10 as positive and negative control groups showed degree of tubular damage 3 ± 0.22 and 0 ± 0 respectively. The arrows indicated tubular damage