Attenuation of puromycin aminonucleoside-induced glomerular lesions in rats by CGS 26303, a dual neutral endopeptidase/endothelin-converting enzyme inhibitor

Endothelin-1 (ET-1) has been implicated in the pathogenesis of various rena l diseases. The purpose of this study was to investigate the effect of CGS 26303, an endothelin-converting enzyme (ECE) inhibitor, on puromycin aminon ucleoside (PA)-induced nephrosis in rats. The animals (three groups; n=8 pe r group) received 50 mg/kg PA or NaCl, intravenously. CGS 26303 (5 mg/kg/da y, s.c. via osmotic minipumps) or vehicle was administered to the PA-treate d animals for 4 weeks, starting within 5 min after PA injection. Uninephrec tomy was performed 2 weeks after PA to accelerate the renal damage. Rats re ceived no treatment between 4 and 8 weeks. At 8 weeks rats were euthanized and kidneys removed for histology and analysis for mRNA levels of endotheli n-A- and -B- (ETA and ETB) receptors and ECE-1. Glomeruli (100 glomeruli/se ction; 800/group) were graded as normal (N), mild lesion (ML=few periodic a cid-Schiff positive [PAS(+)] droplets and small adhesions to Bowman's capsu le), and moderate to severe lesion (SL = many PAS(+) droplets, adhesions to and thickening of Bowman's capsule, mesangial expansion, and cystic dilati ons of glomerular capillaries). In the PA + vehicle group N, ML and SL were 39.5%, 11.9% and 48.6%, respectively, while the respective values were 68. 3%, 9.4%, and 22.3% in PA + CGS 26303-treated rats. However, the renal mRNA levels of ECE-1 and ETA- and ETB-receptors were not significantly differen t among the three groups. These results confirm the efficacy of ECE inhibit ion in this disease model. On the other hand, the mRNA data suggest that ei ther there was no change in the expression of the genes examined or their l evels had already returned to normal by the end of the experiment.