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

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gp130信号转导组分密切相关，它也可能在外周组织中作为促炎细胞因子。在此，我们研究了瘦素作为促炎细胞因子在小鼠单侧输尿管梗阻（UUO）引起的肾脏炎症和纤维化中的病理生理作用。野生型小鼠的梗阻肾增大，显示出残留皮质的薄边缘。相比之下，瘦素缺乏的ob/ob小鼠大部分肾实质得以保留。通过马氏三色染色，我们发现ob/ob小鼠的肾纤维化相对于野生型小鼠是被阻止的。与野生型小鼠相比，瘦素受体突变的db/db小鼠的肾脏炎症和纤维化也得到了预防。对梗阻肾中的基因表达分析显示，相对于野生型小鼠，ob/ob小鼠的细胞因子、巨噬细胞标志物和纤维化均受到抑制。当用瘦素治疗时，ob/ob小鼠肾脏炎症和纤维化的改善逆转，而db/db小鼠则逆转，提示瘦素受体介导的作用。通过培养单核细胞和肾上皮细胞，我们也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，瘦素缺乏可改善uuo诱导的肾脏炎症和纤维化，这可能不是通过直接影响骨髓源性细胞和肾上皮细胞来介导的。

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.