Role of prostanoids and endothelins in the prevention of cyclosporine-induced nephrotoxicity.

Cyclosporine A nephrotoxicity includes both functional toxicity and histological changes, whose seriousness is dependent upon the dose and the duration of the drug administration. Several vasoactive agents have been found to be implicated in cyclosporine induced nephrotoxicity, among which prostanoids and endothelins are the most important. In previous studies we were able to prevent the early stage (7 days) of cyclosporine (37.4 micromol [45 mg]/kg/day) induced nephrotoxicity in rats either by the administration, i) of OKY-046, a thromboxane A(2)synthase inhibitor, ii) of ketanserine, an antagonist of S(2)serotonergic, a(1)adrenergic, and H(1)histaminergic receptors and iii) of nifedipine, a calcium channel blocker, or by diet supplementation either with evening primrose oil or fish oil. All these protective agents elevated ratios of excreted renal prostanoid vasodilators (prostaglandins E(2), 6ketoF(1 alpha)) to vasoconstrictor (thromboxane B(2)), a ratio which was decreased by the administration of cyclosporine alone. Nifedipine averted the cyclosporine induced increase of urinary endothelin-1 release. All protections were associated with the reinstatement of glomerular filtration rate forwards normal levels whereas renal damage defence, consisting of a decrease of the cyclosporine induced vacuolizations, was variable. Ketanserine and evening primrose oil were the only agents which prevented the animal body weight loss. These data suggest that prostanoids and endothelin-1 may mediate functional toxicity while thromboxane A(2)is involved the morphological changes too, provoked in the early stage of cyclosporine treatment. However, other nephrotoxic factors and additional mechanisms could also be implicated in the cyclosporine induced nephrotoxicity.

Effects of OKY-046 and nifedipine in cyclosporine-induced renal dysfunction in rats.

Cyclosporine (CsA) (37.4 mumol/kg per day for 7 days) treated female Wistar rats exhibited significantly decreased creatinine clearance (Ccr) and body weight loss (BWL), but had neither proteinuria (PU) nor alteration in their urine volume (V). Light microscopic (LM) sections of rat kidneys showed that all kidneys were affected by lesions, mainly diffuse vacuolization. These changes were associated with decreased urinary excretion ratios of 6-ketoprostaglandin F1 alpha to thromboxane B2 (6kPGF1 alpha/TXB2) and prostaglandin E2 to TXB2 (PGE2/TXB2). When OKY-046, a TXA2-synthetase inhibitor or nifedipine (NFD), a calcium channel blocker and an antagonist of endotheline (ET), were administered in addition to CsA, they restored Ccr and increased urine V but they did not prevent BWL. LM sections showed that only 5 or 7 out of 9 kidneys of animals were affected, respectively. These changes were associated with prevention of the diminished ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 mainly in the OKY-046 treated animals. In conclusion, our results suggest that inhibitors of TXA2 or antagonists and/or inhibitors of endothelin play a protective role in the development of the dysfunction induced by CsA. However, the protection observed using OKY-046 and NFD did not reach that obtained by evening primrose oil (EPO) or Ketanserine (KTS), substances which prevented the fall of Ccr and BWL. Furthermore, with these protective agents only 5 out of 9 kidneys were affected and the lesions were of minor importance.

Alteration of cyclosporine (CsA)-induced nephrotoxicity by gamma linolenic acid (GLA) and eicosapentaenoic acid (EPA) in Wistar rats.

Administration of cyclosporine (CsA), 37.4 microM (45 mg)/Kg, per day for 7 days, to Wistar rats, induced decreased creatinine clearance (Ccr) and body weight loss (BWL), but it did not induce proteinuria. These changes were associated with enhanced urinary thromboxane B2 (TXB2) and diminished 6-keto-PGF1 alpha (6kPGF1 alpha) and prostaglandin E2 (PGE2) excretions. The augmentation in TXB2 and the decrease in PGs highly diminished the ratios of 6kPGF1 alpha/TXB2 and PGE2/TXB2. In microscopic sections all of the kidneys were affected to variable degrees. When CsA was administered to animals fed for 70 days, prior to the experiment, on standard chow (SC) containing evening primrose oil (EPO) or fish oil (FO), 1% and 10% respectively (EPO contained 9% gamma-linolenic acid (GLA) and FO 5.6% eicosapentaenoic acid (EPA)), the nephrotoxic effect of CsA was partially prevented. These changes were accompanied by increased ratios of urinary 6kPGF1 alpha/TXB2 and PGE2/TXB2 excretions. Light microscopic (LM) studies showed that rats' kidneys fed on SC containing EPO or FO were not always affected and the lesions were of minor importance. In conclusion, these results suggest that EPO (GLA) and FO (EPA) could play a beneficial role in the development or the modulation of the renal syndrome induced by CsA.