Remuzzi G, Imberti L, Rossini M, Morelli C, Carminati C, Cattaneo G M, Bertani T
J Clin Invest. 1985 Jan;75(1):94-101. doi: 10.1172/JCI111703.
Altered glomerular metabolism of arachidonic acid (AA) has already been demonstrated in experimental nephrotoxic nephritis. The enhanced synthesis of thromboxane A2 (TxA2) in isolated glomeruli that has been found may mediate changes in renal hemodynamics. The objectives of this investigation were: to check whether glomerular AA metabolism is also altered in a model of glomerulopathy in which no leukocyte infiltration or platelet deposition could be demonstrated; to establish a correlation between the altered AA metabolism and proteinuria; and to explore whether the alteration of the prostaglandin (PG) pathway found in isolated glomeruli is an in vitro artifact or reflects a modification in vivo. We used a model of glomerular damage characterized by heavy and persistent proteinuria, which was induced in the rat by a single intravenous injection of adriamycin. At light microscopy, minimal glomerular abnormalities were found in this model. Electron microscopy showed profound alterations of glomerular epithelial cells with extensive fusion of foot processes and signs of epithelial cell activation. Electron microscopy of numerous glomeruli showed no platelet deposition or macrophage and leukocyte infiltration in this model. Isolated glomeruli from nephrotic rats studied 14 or 30 d after a single intravenous injection of adriamycin (7.5 mg/kg) when animals were heavily proteinuric generated significantly more TxB2, the stable breakdown product of TxA2, than normal glomeruli. No significant changes were found in the other major AA metabolites formed through cyclooxygenase. Urinary excretion of immunoreactive TxB2 was also significantly higher in nephrotic than in normal animals. Administration of a selective Tx synthetase inhibitor, UK-38,485, from day 14 to day 18 after adriamycin resulted in a significant reduction of proteinuria compared with pretreatment values. Glomerular synthesis and urinary excretion of TxB2 were normal during the UK-38,485 treatment. Additional experiments showed that elevated glomerular synthesis and urinary excretion of TxB2 were not a consequence of increased substrate availability. Maximal stimulation of the renin-angiotensin axis with furosemide increased glomerular TxB2 synthesis in normal rats, which was significantly lower than in nephrotic animals. Finally, experiments using a unilateral model of adriamycin nephrosis indicated that the enhancement of glomerular TxB2 synthesis is not simply a consequence of the nephrotic syndrome. We conclude that: there is an abnormality of glomerular AA metabolism in nephritic syndrome, which leads to increased TxA2 production; the increased Tx generation correlates with protein excretion and might be responsible for altering the glomerular basement membrane permeability to protein; and the alteration found in isolated glomeruli probably reflects a modification in vivo, in that urinary excretion of immunoreactive TxB2 is also consistently increased in adriamycin nephrosis.
花生四烯酸（AA）肾小球代谢改变已在实验性肾毒性肾炎中得到证实。已发现分离的肾小球中血栓素A2（TxA2）合成增强，这可能介导肾血流动力学的变化。本研究的目的是：检查在一个无白细胞浸润或血小板沉积的肾小球病模型中，肾小球AA代谢是否也发生改变；确定AA代谢改变与蛋白尿之间的相关性；探讨在分离的肾小球中发现的前列腺素（PG）途径改变是体外假象还是反映体内的变化。我们使用了一种以大量持续性蛋白尿为特征的肾小球损伤模型，该模型通过给大鼠单次静脉注射阿霉素诱导产生。在光学显微镜下，该模型中肾小球异常轻微。电子显微镜显示肾小球上皮细胞有深刻改变，足突广泛融合且有上皮细胞活化迹象。对众多肾小球的电子显微镜检查显示，该模型中无血小板沉积或巨噬细胞及白细胞浸润。在单次静脉注射阿霉素（7.5mg/kg）14或30天后，当动物出现大量蛋白尿时，从肾病大鼠分离的肾小球产生的TxA2稳定分解产物血栓素B2（TxB2）明显多于正常肾小球。通过环氧化酶形成的其他主要AA代谢产物未发现显著变化。肾病大鼠尿中免疫反应性TxB2的排泄也明显高于正常动物。从阿霉素注射后第14天至第18天给予选择性Tx合成酶抑制剂UK - 38,485，与预处理值相比，蛋白尿显著减少。在UK - 38,485治疗期间，肾小球TxB2的合成和尿排泄正常。额外实验表明，肾小球TxB2合成和尿排泄升高不是底物可用性增加的结果。用速尿最大程度刺激肾素 - 血管紧张素轴可增加正常大鼠肾小球TxB2合成，但明显低于肾病动物。最后，使用阿霉素肾病单侧模型的实验表明，肾小球TxB2合成增强不仅仅是肾病综合征的结果。我们得出结论：肾病综合征存在肾小球AA代谢异常，导致TxA2生成增加；Tx生成增加与蛋白质排泄相关，可能是导致肾小球基底膜对蛋白质通透性改变的原因；在分离的肾小球中发现的改变可能反映体内变化，因为在阿霉素肾病中尿中免疫反应性TxB2排泄也持续增加。
