Thromboxane receptor blockade attenuates chronic cyclosporine nephrotoxicity and improves survival in rats with renal isograft

Norberto Perico, Magda Rossini, Ornella Imberti, Barbara Malanchini, Paul Plata Cornejo, Flavio Gaspari, Tullio Bertani, Giuseppe Remuzzi

Research output: Contribution to journalArticlepeer-review

Abstract

The question of whether pharmacological inhibition of the thromboxane A2 activity prevents cyclosporine-induced chronic renal dysfunction in a Lewis rat model of renal isograft was addressed. Transplanted animals were given a daily oral dose of cyclosporine (20 mg/kg; N= 15), cyclosporine (20 mg/kg) and the thromboxane A2 receptor antagonist GR32191 (3 mg/kg twice daily, by gavage; N= 15), or the vehicle alone (N= 12). Treatments were started the day of kidney transplant, and animals were monitored for 1 year. Cyclosporine-treated animals developed renal insufficiency, as documented by serum creatinine levels of 0.49 ± 0.09, 0.95 ± 0.12, and 1.38 ± 0.15 mg/dL before and after 6 and 12 months of observation, respectively. Cyclosporine and GR32191 used in combination partially but significantly prevented the deterioration of renal function (serum creatinine, basal, 0.52 ± 0.06; month 6, 0.68 ± 0.04; month 12, 0.93 ± 0.10 mg/dL). At the end of the study, GFR, as inulin clearance, was significantly lower in rats given cyclosporine (0.28 ± 0.09 mL/min/ 100 g) than in rats given cyclosporine plus GR32191 (0.45 ± 0.05 mL/min/100 g) or than in vehicle-treated animals (0.56 ± 0.07 mL/min/100 g). Similar results were obtained for the effective RPF, measured as p-aminohippurate clearance. At the same time points, comparable to whole-blood cyclosporine levels were found in rats receiving cyclosporine alone and in those given cyclosporine plus GR32191. More than 50% of the animals on cyclosporine alone died from uremia before the end of the observation period. By contrast, rats receiving cyclosporine in combination with GR32191 had a prolonged survival. These findings indicate that limiting the functional consequence of excessive thromboxane A2 synthesis in a rat isograft model prevents the long-term consequences of cyclosporine renal toxicity and increases the survival of transplanted animals.

Original languageEnglish
Pages (from-to)1398-1404
Number of pages7
JournalJournal of the American Society of Nephrology
Volume2
Issue number9
Publication statusPublished - Mar 1992

Keywords

  • GFR
  • Renal insufficiency
  • RPF

ASJC Scopus subject areas

  • Nephrology

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