权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pathophysiologic and therapeutic implication of leptin as a pro-inflammatory cytokine

瘦素作为促炎细胞因子的病理生理学和治疗意义

基本信息

批准号：
17390268
负责人：
OGAWA Yoshihiro
金额：
$ 9.66万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390268/
关键词：
leptin monocytes unilateral ureteral obstruction renal epithelial cells ob ob mice db db mice レプチン受容体炎症線維化一側尿管結紮腎障害骨髄細胞炎症性サイトカイン腎間質線維化

项目摘要

Leptin is an important adipocytokine that acts directly on the hypothalamus and regulates food intake and energy expenditure. Because leptin receptor is closely related to the gp130 signal-transduction component of class I cytokine receptors, it may also act as a pro-inflammatory cytokine in the peripheral tissues. Here we examined the pathophysiologic role of leptin as a pro-inflammatory cytokine in renal inflammation and fibrosis induced by unilateral ureteral obstruction (UUO) in mice. The obstructed kidney of the wildtype mice was enlarged and exhibited a thin rim of the remaining cortex. By contrast, most of the renal parenchyma was preserved in leptin deficient ob/ob mice. By Masson's Thrichrome staining, we found that the renal fibrosis in ob/ob mice is prevented relative to the wildtype mice. The renal inflammation and fibrosis were also prevented in db/db mice with a leptin receptor mutation relative to the wildtype mice. Analysis of the gene expression in the obstructed kidney revealed that cytokines, markers of macrophages, and fibrosis are all suppressed in ob/ob mice relative to wildtype mice. The improvement of renal inflammation and fibrosis were reversed in ob/ob mice but in db/db mice, when treated with leptin, suggesting the leptin receptor-mediated effect. Using cultured monocytes and renal epithelial cells, we also found that leptin does not induce inflammatory responses via direct mechanism. These observations suggest that leptin deficiency improves the UUO-induced renal inflammation and fibrosis, which may not be mediated through the direct effect on bone marrow-derived cells and renal epithelial cells.

瘦素是一种重要的脂肪细胞因子，直接作用于下丘脑，调节食物摄入和能量消耗。由于瘦素受体与I类细胞因子受体的gp 130信号转导组分密切相关，因此它也可以在外周组织中充当促炎细胞因子。在此，我们研究了瘦素作为一种促炎细胞因子在单侧输尿管梗阻（UUO）诱导的小鼠肾脏炎症和纤维化中的病理生理作用。野生型小鼠阻塞的肾脏增大，并显示出剩余皮质的薄边缘。相比之下，瘦素缺陷型ob/ob小鼠的大部分肾实质得以保留。通过Masson三色染色，我们发现相对于野生型小鼠，ob/ob小鼠的肾纤维化被阻止。相对于野生型小鼠，具有瘦素受体突变的db/db小鼠的肾脏炎症和纤维化也被预防。对阻塞肾脏中基因表达的分析显示，相对于野生型小鼠，ob/ob小鼠中的细胞因子、巨噬细胞标志物和纤维化都受到抑制。瘦素治疗后，ob/ob小鼠肾脏炎症和纤维化的改善被逆转，但在db/db小鼠中，提示瘦素受体介导的作用。利用培养的单核细胞和肾上皮细胞，我们还发现瘦素不通过直接机制诱导炎症反应。这些观察结果表明，瘦素缺乏改善UUO诱导的肾脏炎症和纤维化，这可能不是通过对骨髓源性细胞和肾上皮细胞的直接作用介导的。