To shed light on the role of thromboxane A2 (TXA2) in renal injury, we evaluated the effects of S-1452, a TXA2 receptor antagonist, on rats with streptozotocin (STZ)-induced diabetic nephropathy and murine lupus nephritis. In STZ diabetes rats (n = 6), urinary protein excretion significantly increased from 8 weeks and was about 5 times as much as that in normal rats at 10 weeks after induction of diabetes. In S-1452-treated rats (n = 6), increase in urinary protein was rarely observed and was significantly inhibited at 8 and 10 weeks after induction of diabetes. In (NZB × NZW)F1 mice, no proteinuria was detected in vehicle controls (n = 20) and S-1452-treated mice (n = 20) from 0 to 8 weeks after initiation of S-1452 treatment. Proteinuria was observed in 3, 7 and 8 mice in the control group, and 0, 2 and 5 mice in the S-1452 group at 12, 16 and 20 weeks after initiation of S-1452 treatment, respectively. Proteinuria developed more slowly in S-1452-treated mice than in vehicle controls. In conclusion, TXA2 receptor antagonist, S-1452, suppresses the progression of renal injury.
ABSTRACT-The therapeutic effects of angiotensin converting enzyme inhibitor, lisinopril, on puromycin aminonucleoside (PAN)-induced nephrosis were investigated using unilaterally nephrectomized rats. Lisinopril showed potent dual effects on PAN nephrosis. Lisinopril treatment (50 mg/l in drinking water) from day 5 or day 9 reduced urinary protein excretion and suppressed the development of glomerular sclerosis at 8 weeks after PAN injection (150 mg/kg, i.p.), indicating a therapeutic effect on the nephrosis. Recovery of decreased anionic charge sites on the glomerular basement membrane was involved, at least in part, in the therapeutic action of lisinopril against proteinuria. On the other hand, oliguria and progressive azotemia derived from continuous deterioration of the renal function was induced if the treatment of lisinopril was started on the same day as PAN injection. The renal dysfunction induced by simultaneous administration of lisinopril with PAN could be abolished by combination dosing with sarcosine, an angio tensin II (AII)-receptor agonist. These results indicate that lisinopril treatment attenuates proteinuria by ameliorating the anionic charge barrier on the glomerular basement membrane and that it also protects against the development of chronic renal disease with segmental glomerular sclerosis, although All deple tion during the acute nephrotic stage exacerbates the renal damage in PAN nephrosis of unilaterally nephrectomized rats.
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