Prevention of glomerulosed erosis and tubul ointerstitial fibrosis : the effect of antisense ologonucleotide of type I procollagen C-proteinase enhancer protein

众所周知，无论基础疾病是什么，进行性肾损伤的特点是肾小球侵蚀和肾小管间质纤维化，这是慢性肾功能衰竭的共同病理特征。我们计划进行本研究以探讨肾脏纤维化的机制。首先，我们检测了研究人员之一Ogata I最近克隆的I型前胶原C-蛋白酶增强子蛋白PCPE的表达。这位作者已经证明PCPE在肝纤维化中起着重要作用。我们利用培养的大鼠肾小球系膜细胞、正常大鼠肾脏和5/6肾切除大鼠肾脏，通过Western印迹分析检测了其在肾脏中的表达，但未检测到其在肾脏中的表达。我们还用Northern印迹分析检测了它的mRNA表达，也没有检测到。因此，我们得出结论，PCPE在肾脏纤维化的发病机制中只起到很小的作用。我们还研究了白三烯B4(LTB4)在肾脏疾病进展中的作用。建立高脂血症大鼠肾损伤模型，并用LTB4拮抗剂进行治疗。这种治疗明显改善了这些动物的肾脏损伤。然后我们研究了白三烯A4水解酶在大鼠肾段的表达分布，发现白三烯A4水解酶在肾小球和肾小管段均有表达。这些结果提示，肾脏合成的LTB4在进行性肾损伤的发病机制中起重要作用。

It is well known that, whatever the underlying original disease, progressive renal injury is characterized by glomeruloscl erosisand tubulointerstitial fibrosis, which are the common pathological features of chronic renal failure. We have planned the present study to investigate the mechanism of fibrosis in the kidney.First we examined the expression of type I procollagen C-proteinase enhnacer protein, PCPE, which was recently cloned by one of the investigators, Ogata I.By the same author PCPE has been to shown to play an important role in liver fibsosis. We have examined its expression in the kidney by Western blot analysis using cultured rat mesangial cells, normal rat kidney, and 5/6 nephrectomized rat kidney, and we could not detect its expression in the kidney. We also examined the expression of its mRNA by Northern blot analysis, and we could not detect it, neither. So we have concluded that PCPE plays minor role in the pathogenesis of renal fibrosis.We also examined the role of leukotrine B4(LTB4)in the progression of renal diseases. We made hyperlipidemia-induced renal injury in rats, and treated these rats with LTB4 antagonist. This treatment markedly ameliorated kidney injury in these animals. Then we examined the distribution of leukotriene A4 hydrolase mRNA expression in rat nephronsegments, and found that it is present both in glomeruli and tubular segments. These result suggest the important role of LTB4 synthesized in the kidney in the pathogenesis of progressive renal injuries.