Assessment of protective effect of the losartan against cisplatin-induced nephrotoxicity in mice

TL;DR

Losartan reduces kidney damage caused by cisplatin in mice by lowering cell death and boosting tissue repair.

Contribution

This study demonstrates losartan's protective effects against cisplatin-induced nephrotoxicity through reduced apoptosis and enhanced tubular regeneration.

Findings

Losartan significantly reduced glomerular and tubular injury scores in mice treated with cisplatin.

Losartan decreased active caspase-3 expression and increased BrdU-positive cell counts, indicating reduced apoptosis and enhanced regeneration.

These findings suggest RAAS inhibition may prevent cisplatin-associated renal injury.

Abstract

Cisplatin is widely used in pediatric oncology but is limited by its dose-dependent nephrotoxicity. The renin–angiotensin–aldosterone system (RAAS) has been implicated in cisplatin-induced renal injury. Losartan, an angiotensin II receptor blocker, may offer renal protection; however, its effects on apoptosis and regeneration in this context remain unclear. This study aimed to investigate the potential protective role of losartan against cisplatin-induced nephrotoxicity, specifically by assessing its impact on apoptosis and tubular regeneration. Fifteen female BALB/c mice were randomly assigned to three groups (n = 5 per group): Control, cisplatin (12.7 mg/kg, i.p., single dose), and cisplatin + losartan (10 mg/kg/day, oral). Losartan was administered for nine consecutive days, starting 4 days before cisplatin exposure. Histopathological examination, active caspase-3 immunostaining (for apoptosis), and 5-bromo-2-deoxyuridine (BrdU) labeling (for cell proliferation) were performed. Glomerular and tubular injury scores, caspase-3 H-scores, and BrdU-positive cell counts were statistically analyzed using the Kruskal–Wallis H and Mann–Whitney U tests. Cisplatin significantly increased glomerular (p = 0.006, p = 0.005, p = 0.006) and tubular injury scores (p = 0.008, p = 0.007, p = 0.007, p = 0.007, p = 0.007), elevated active caspase-3 expression (p = 0.002), and reduced BrdU-positive cell counts (p = 0.009) compared to control. Losartan co-treatment significantly reduced glomerular (p = 0.008, p = 0.005, p = 0.008) and tubular injury (p = 0.008, p = 0.008, p = 0.009, p = 0.008, v) and decreased caspase-3 expression (p = 0.009). Additionally, BrdU-positive cell counts were significantly higher in the cisplatin + losartan group compared to both control and cisplatin groups (p = 0.009), indicating enhanced regeneration. Losartan mitigates cisplatin-induced nephrotoxicity by suppressing apoptosis and promoting tubular regeneration. These findings support the potential therapeutic role of RAAS inhibition in preventing cisplatin-associated renal injury.

Figures