A role for leukotrienes in cyclosporine nephrotoxicity

Background. Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis, and arteriolar hypertrophy. While the molecular mechanisms of CsA toxicity are not well characterized, previous studies have demonstrated that altered arachidonic acid (AA) metabolism plays a role its pathogenesis. Using a rat renal transplant model, the purpose of this study was to examine the effects of CsA on the 5-lipoxygenase (5-LO) pathway of AA metabolism. Methods. The PVG (RT1c) strain of rats underwent kidney transplantation, and recipients of nonrejecting kidney transplants were treated with either 50 mg/kg/day CsA or vehicle (N = 24). To determine the physiologic significance of increased leukotriene (LT) production, the peptidoleukotriene receptor antagonist SKF 106203 was administered to CsA- treated animals for six days. Results. CsA caused a substantial reduction in glomerular filtration rate (GFR) in the transplanted rats compared with the vehicle-treated controls (1.5 ± 0.6 vs. 4.1 ± 0.8 mL/min/kg, P < 0.05). The reduction in renal function was associated with enhanced urinary excretion of the peptidoleukotriene metabolites LTE₄ (1431 ± 207 vs. 953 ± 125 pg/24 h, P < 0.05) and N-acetyl-LTE₄ (4411 ± 848 vs. 463 ± 70 pg/24 h, P < 0.001). LT receptor blockade had a significant protective effect on renal transplant function in CsA-treated animals (GFR, 4.8 ± 1.1 vs. 1.7 ± 0.9 mL/min/kg, P < 0.05), such that CsA-treated animals that received SKF106203 maintained GFR at levels similar to controls that never received CsA (4.1 ± 0.8 mL/min/kg). Peptidoleukotriene receptor blockade also prevented the histomorphological abnormalities caused by CsA, including tubular vacuolization. Conclusions. These studies identify a critical role for LTs in the pathophysiology of CsA nephrotoxicity and suggest that LT antagonists may be useful in preventing CsA-associated kidney toxicity.