THE ROLE OF THE RENIN-ANGIOTENSIN SYSTEM IN CISPLATIN NEPHROTOXICITY

The role of the renin-angiotensin system (RAS) in; the pathogenesis of cisplatin nephrotoxicity was evaluated in an experimental rat model u sing a specific, nonpeptide angiotensin II (AII) receptor blocker losa rtan. Rats were treated with a single dose of losartan (at 10 mg/kg an d 30 mg/kg, i.p.) or saline, 2 h prior to cisplatin administration (5 mg/kg, i.p.). Renal function was assessed 3 and 7 days after cisplatin treatment. A second group of rats received losartan (10 mg/kg, i.p.) or saline, 2 h prior to cisplatin administration (5 mg/ kg, i.p.), and losartan (10 mg/kg, i.p.) or saline daily for 6 days after cisplatin treatment. Renal function was assessed on day 7. Neither high- nor low -dose losartan pretreatment prevented development of cisplatin-induced nephrotoxicity. Blood urea nitrogen (BUN) and plasma creatinine value s at 7 days were similar to those of animals receiving cisplatin alone (BUN: 17.12 +/- 1.1 and 22.17 +/- 2.2 vs. 20.58 +/- 2.4 mg/dL; creati nine: 1.04 +/- 0.05 and 0.82 +/- 0.09 vs. 0.84 +/- 0.06 mg/dL). A sign ificant reduction in creatinine clearance with cisplatin treatment was seen 3 days after therapy, which was not prevented by pretreatment wi th losartan (GFR in controls: 2.1 +/- 0.16 mL/min; cisplatin: 0.24 +/- 0.05; cisplatin plus low-dose losartan: 0.05 +/- 0.03 and cisplatin p lus high-dose losartan: 0.37 +/- 0.05). All groups of cisplatin-treate d rats displayed systemic signs of cisplatin toxicity: reduced food in take and body weight. Rats receiving chronic losartan treatment had mo re rapid weight gain and lower BUN and plasma creatinine levels on day 7 than rats receiving cisplatin alone (BUN: 24.0 +/- 2.64 vs. 36.4 +/ - 0.91 mg/dL; p < 0.05; plasma creatinine: 0.86 +/- 0.06 vs. 1.15 +/- 0.07 mg/dL; p < 0.05). Acute blockade of the AII receptor with losarta n does not alter the onset or severity of cisplatin nephrotoxicity. Ch ronic blockade of the AII receptor may improve the rate of recovery of renal function in cisplatin-treated rats.