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.

瘦素是直接作用于下丘脑并调节食物摄入和能量消耗的重要脂肪细胞因子。由于瘦素受体与I类细胞因子受体的GP130信号转移成分密切相关，因此它也可以充当外周组织中的促炎性细胞因子。在这里，我们研究了小鼠单侧输尿管阻塞（UUO）诱导的肾脏炎症和纤维化中瘦素作为促炎细胞因子的病理生理作用。野生型小鼠的阻塞肾脏被扩大，并表现出剩余的皮质的细边缘。相比之下，大多数肾实质保留在瘦素缺乏的OB/OB小鼠中。通过Masson的三色染色，我们发现相对于野生型小鼠而言，OB/OB小鼠的肾纤维化是预防的。还可以防止肾脏受体突变相对于野生型小鼠，肾脏炎症和纤维化也可以预防。对受阻肾脏中基因表达的分析表明，相对于野生型小鼠，OB/OB小鼠的细胞因子，巨噬细胞的标志物和纤维化均被抑制。 ob/ob小鼠中肾脏炎症和纤维化的改善被逆转，但在用瘦素治疗时，在DB/DB小鼠中，肾脏炎症和纤维化的改善表明瘦素受体介导的作用。使用培养的单核细胞和肾上皮细胞，我们还发现瘦素不会通过直接机制诱导炎症反应。这些观察结果表明，瘦素缺乏改善了UUO诱导的肾脏炎症和纤维化，这可能不会通过直接对骨髓衍生细胞和肾上皮细胞的直接作用来介导。