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

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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.