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）和血栓素（TX） A_2等脂质类自体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微解剖肾元段、培养肾素源性细胞如肾小球系膜细胞、基因靶小鼠和肾脏疾病患者DNA样本进行了分子和细胞生物学研究，结果如下：(1)利用新的显微解剖片段定量RT-PCR方法（MRT-PCR），我们发现PAF和TXA_2受体mRNA在肾元中普遍分布；(2)PAF诱导培养的肾小球系膜细胞产生PGE_2形成cAMP，从而介导PAF受体mRNA表达的同源下调；(3)PAF受体基因靶向小鼠在糖尿病和顺铂肾病发病中的病理生理作用，但然而，(4)PAF乙酰水合酶基因多态性与糖尿病肾病的发病和/或进展之间的相关性尚不明确。这些结果将导致新的认识脂质类autotacoids在肾脏中的意义。

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.