Stable analogs of prostaglandins E1 and F2 alpha ameliorate the proteinuria of aminonucleoside-of-puromycin nephrosis in Lewis rats.
Prostaglandins have been implicated by previous investigators in the pathogenesis of the nephrotic syndrome. A single subcutaneous injection of 1 mg/kg of stable analogs of prostaglandins E1 or F2 alpha (15[S]-15-methyl -PGE1 [M-PGE1] and -PGF2 alpha [M-PGF2 alpha]) was found in the present study to dramatically decrease proteinuria on Day 10 of puromycin aminonucleoside (PAN) nephrosis in Lewis rats. The decrease in proteinuria was mediated at least in part by a decrease in glomerular filtration rate (GFR), as quantitated by inulin clearances in nephrotic control and prostaglandin-treated rats. M-PGE1, moderately, and M-PGF2 alpha, to a lesser degree, also decreased the GFR in normal rats. Interestingly, the GFR was dramatically decreased in nephrotic as compared with nonnephrotic control rats, which suggests that PAN nephrosis may not be an ideal experimental model for human minimal change nephrosis in which the GFR is usually not severely compromised. The prostaglandin-induced decrease in GFR in both nephrotic and normal rats was coincident with a drop in systemic blood pressure. Nephrotic rats, however, had a slightly higher baseline blood pressure than normals, and the hypotensive effects of both prostaglandins were much less in nephrotic than in normal rats. The decrease in proteinuria was not related to a cytoprotective effect, as indicated by the failure of daily doses of 5 micrograms/kg M-PGE1 to reduce proteinuria 6, 8, or 10 days after injection of puromycin aminonucleoside. The similar antiproteinuric effects of prostaglandin synthesis inhibitors and of pharmacologic doses of prostaglandins are somewhat paradoxical but are reminiscent of the similarly paradoxical mutual antiinflammatory effects of these agents. The high doses of prostaglandins required to reduce proteinuria as well as their reduction of blood pressure and GFR will limit their clinical usefulness in the nephrotic syndrome.
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002260:Carboprost / Q000627:therapeutic use*; D004231:Diuresis / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D011461:Prostaglandins F, Synthetic / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D011692:Puromycin Aminonucleoside; D051381:Rats; D011917:Rats, Inbred Lew
D011461:Prostaglandins F, Synthetic; C025170:15(S)-15-methylprostaglandin E1; D011692:Puromycin Aminonucleoside; D002260:Carboprost; D000527:Alprostadil