Ulich T R, Meline J A, Ni R X, Keys M, Wu C H
Department of Pathology, University of California, Irvine Medical School 92717.
Am J Pathol. 1987 Oct;129(1):133-9.
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.
以往的研究人员认为前列腺素与肾病综合征的发病机制有关。在本研究中发现，给Lewis大鼠单次皮下注射1mg/kg前列腺素E1或F2α的稳定类似物（15[S]-15-甲基-PGE1 [M-PGE1]和-PGF2α [M-PGF2α]），在嘌呤霉素氨基核苷（PAN）肾病第10天时可显著降低蛋白尿。蛋白尿的减少至少部分是由肾小球滤过率（GFR）降低介导的，这通过肾病对照组和前列腺素治疗组大鼠的菊粉清除率来定量。M-PGE1在一定程度上，M-PGF2α在较小程度上也降低了正常大鼠的GFR。有趣的是，与非肾病对照组大鼠相比，肾病大鼠的GFR显著降低，这表明PAN肾病可能不是人类微小病变肾病的理想实验模型，因为在人类微小病变肾病中GFR通常不会受到严重损害。前列腺素诱导的肾病大鼠和正常大鼠GFR降低与全身血压下降同时发生。然而，肾病大鼠的基线血压略高于正常大鼠，两种前列腺素的降压作用在肾病大鼠中比在正常大鼠中要小得多。蛋白尿的减少与细胞保护作用无关，因为每天注射5μg/kg M-PGE1并不能在注射嘌呤霉素氨基核苷后6、8或10天减少蛋白尿。前列腺素合成抑制剂和药理剂量的前列腺素具有相似的抗蛋白尿作用，这有点自相矛盾，但让人想起这些药物同样自相矛盾的相互抗炎作用。降低蛋白尿所需的高剂量前列腺素以及它们对血压和GFR的降低作用将限制它们在肾病综合征中的临床应用。
