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 renal diseases. The purpose of this study was to investigate the effect of CGS 26303, an endothelin-converting enzyme (ECE) inhibitor, on puromycin aminonucleoside (PA)-induced nephrosis in rats. The animals (three groups; n = 8 per group) received 50 mg/kg PA or NaCl, intravenously. CGS 26303 (5 mg/kg/day, s.c. via osmotic minipumps) or vehicle was administered to the PA-treated animals for 4 weeks, starting within 5 min after PA injection. Uninephrectomy was performed 2 weeks after PA to accelerate the renal damage. Rats received no treatment between 4 and 8 weeks. At 8 weeks rats were euthanized and kidneys removed for histology and analysis for mRNA levels of endothelin-A- and -B- (ET(A) and ET(B)) receptors and ECE-1. Glomeruli (100 glomeruli/section; 800/group) were graded as normal (N), mild lesion (ML = few periodic acid-Schiff positive [PAS+] droplets and small adhesions to Bowman's capsule), and moderate to severe lesion (SL = many PAS+ droplets, adhesions to and thickening of Bowman's capsule, mesangial expansion, and cystic dilations 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 ET(A)- and ET(B)-receptors were not significantly different among the three groups. These results confirm the efficacy of ECE inhibition in this disease model. On the other hand, the mRNA data suggest that either there was no change in the expression of the genes examined or their levels had already returned to normal by the end of the experiment.
Feldman
D L
DL
Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA. david.feldman@pharma.novartis.com
Mogelesky
T C
TC
Chou
M
M
Jeng
A Y
AY
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015152:Blotting, Northern; D000072396:Endothelin-Converting Enzymes; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011507:Proteinuria / Q000188:drug therapy; D011692:Puromycin Aminonucleoside / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology*
D063065:Organophosphonates; D011480:Protease Inhibitors; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013777:Tetrazoles; C089987:CGS 26303; D011692:Puromycin Aminonucleoside; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes