Salvati P, Ferti C, Ferrario R G, Lamberti E, Duzzi L, Bianchi G, Remuzzi G, Perico N, Benigni A, Braidotti P
Farmitalia Carlo Erba, Nerviano, Italy.
Kidney Int. 1990 Sep;38(3):447-58. doi: 10.1038/ki.1990.225.
Normotensive rats of the Milan strain (MNS) spontaneously develop focal glomerulosclerosis. In order to explore the contribution of glomerular thromboxane (TX) A2 synthesis to the development of the disease, we have characterized the time course of renal functional and biochemical changes, and their modification by long-term treatment with a TX-synthase inhibitor. Oral administration (150 mg.kg-1 from 1 to 14 months of age) of FCE 22178 suppressed enhanced glomerular TXB2 production at all experimental times (mean inhibition 80%) and proteinuria (varying between 27.1 and 73.0%) while preserving renal blood flow and glomerular filtration rate. These effects of TX-synthase inhibition were seen in the absence of any statistically significant changes in systemic blood pressure. Moreover, FCE 22178 had no antihypertensive effects in hypertensive rats of the Milan strain (MHS) nor in spontaneously hypertensive rats (SHR). Treatment also prevented the age-related hypoalbuminemia and hyperlipidemia observed in control MNS and significantly (P less than 0.01) reduced glomerular histologic damage, as demonstrated by light microscopy studies and measurement of sclerotic area. We conclude that: 1) MNS rats provide an animal model of long-lasting proteinuria characterized by an age-related increase in glomerular TXB2 production paralleled by progressive loss of renal structural integrity and function and by a secondary dyslipidemia; 2) pharmacological inhibition of glomerular TX-synthase attenuates the structural as well as the functional expression of kidney disease, without a primary effect on systemic blood pressure. These data are suggestive of an important modulating role of TXA2 in the progression of MNS renal disease.
米兰品系（MNS）的血压正常大鼠会自发发展为局灶性肾小球硬化症。为了探究肾小球血栓素（TX）A2合成在该疾病发展过程中的作用，我们已对肾功能和生化变化的时间进程及其通过TX合成酶抑制剂长期治疗后的改变进行了表征。从1至14月龄口服给予（150mg·kg-1）FCE 22178可在所有实验时间抑制肾小球TXB2生成增强（平均抑制率80%）以及蛋白尿（抑制率在27.1%至73.0%之间变化），同时维持肾血流量和肾小球滤过率。在全身血压无任何统计学显著变化的情况下可观察到TX合成酶抑制的这些作用。此外，FCE 22178对米兰品系高血压大鼠（MHS）以及自发性高血压大鼠（SHR）均无降压作用。治疗还预防了在对照MNS中观察到的与年龄相关的低白蛋白血症和高脂血症，并且如通过光学显微镜研究和硬化面积测量所证实的，显著（P小于0.01）降低了肾小球组织学损伤。我们得出结论：1）MNS大鼠提供了一种持续性蛋白尿的动物模型，其特征为肾小球TXB2生成随年龄增长而增加，同时伴有肾脏结构完整性和功能的逐渐丧失以及继发性血脂异常；2）肾小球TX合成酶的药理学抑制可减轻肾脏疾病的结构和功能表现，而对全身血压无主要影响。这些数据提示TXA2在MNS肾脏疾病进展中具有重要的调节作用。
