Involvement of lipid mediators in the pathogenesis of experimental nephrosis in rats: its pharmacological modulation.

Abstract

The administration of a single-injection of Adriamycin (ADR) to rats results in marked proteinuria and glomerular morphological changes that are similar to minimal change disease in humans. We have hypothesized that Adriamycin, by itself or through the release of some mediators from resident glomerular cells, could provoke a damage to epithelial glomerular cells. Sprague-Dawley rats received a single injection of Adriamycin, 7.5 mg/kg bw, allocated randomly in several groups and treated throughout 2 weeks of follow-up. All control nontreated animals developed important nephrotic syndrome and degenerative lesions of epithelial glomerular cells. Isolated glomeruli from animals injected with adriamycin 14 days before synthesized thromboxane (TxB2) and platelet activating factor (PAF) in amounts above the rates of control glomeruli. Animals treated with three structurally different PAF receptor antagonists did not present proteinuria or only to a very low extent (p less than 0.0005). In these rats no alterations in epithelial cells were noted. Furthermore, no significant changes in the TxB2 production were noted in rats treated with BN 52021, a PAF receptor antagonist. Leukotrienes also seem to participate since treatment with a 5-lipoxygenase inhibitor partially corrected proteinuria. Moreover, glomeruli from animals with nephrosis and treated with this compound presented only a discrete reduction in the PAF synthesis. On the whole, these data suggest a key role for PAF in the pathogenesis of adriamycin nephropathy. Other lipid meditors, released in cascade simultaneously or thereafter, could perpetuate the renal damage.