MOLECULAR MECHANISMS OF ACTION AND PHYSIOLOGICAL ROLES OF LIPID AUTACOIDS IN THE NEPHRON

为了阐明血小板活化因子(PAF)和血栓烷(TX)A2等脂质类化合物的作用机制及其生理和病理生理意义，我们对啮齿动物肾脏显微解剖段、培养的肾小球系膜细胞、遗传靶向小鼠和肾脏疾病患者的DNA样本进行了分子和细胞生物学研究。(1)利用我们的新的定量RT-PCR方法(MRT-PCR)，我们证实了PAF和TXA_2受体mRNA在肾单位的广泛分布，(2)PAF受体mRNA的表达下调是由PAF诱导系膜细胞产生PGE_2而形成的cAMP介导的，(3)在PAF受体基因靶向的小鼠中，PAF在糖尿病和顺铂肾病的发病机制中起到了病理生理作用。(4)PAF乙酰水解酶基因多态性与糖尿病肾病发病和/或进展的相关性尚不明显，这些结果将使人们对肾脏类脂蛋白的意义有新的认识。

In order to clarify the action mechanisms and physiological and pathophysiological significances of lipid autacoids such as platelet activating factor (PAF) and thromboxane (TX) A_2, we performed molecular and cellular biological studies in microdissected nephron segments from rodent kidneys, cultured renel-derived cells such as glomerular mesangial cells, genetically target mouse and DNA samples from patients with renal diseases, the results of which are as follows ; (1) Using our new quantitative RT-PCR method (MRT-PCR) in microdissected segments, we demonstrated ubiquitous distribution of PAF and TXA_2 receptor mRNA in the nephron, (2) homologous down-regulation of PAF receptor mRNA expression was shown to be mediated by cAMP formed though PAF-induced PGE_2 production in cultured mesangial cells, (3) pathophysilogical contribution of PAF on the pathogenesis of diabetic and cisplatin nephropathy was demonstrated in PAF receptor gene-targeted mouse, but, however, (4) significant co-relation between polymorphism of PAF acetylhydralase gene and pathogenesis and/or progression of diabetic nephropathy has not been shown so far.These results will lead to new insight to the significances of lipid autacoids in the kidney.