Progressive tubulo-interstitial fibrosis is the common endpoint leading to end-stage renal disease in experimental and clinical settings. Since the peptide hormone leptin is not only involved in the regulation of obesity but also in the regulation of inflammation and fibrosis, we tested the hypothesis whether leptin deficiency has an impact on tubulo-interstitial fibrosis in mice. Leptin-deficient (ob/ob) and leptin receptor-deficient mice (db/db) were exposed to 14 days of unilateral ureteral obstruction (UUO). The degree of fibrosis and inflammation was compared to sham operated mice by immunohistochemistry, Q-PCR and western blotting. We found that tubulo-interstitial fibrosis was significantly reduced in the obstructed kidneys of ob/ob compared to db/db mice or control mice. Detailed analysis of infiltrating inflammatory cells by immunohistochemistry revealed a significant reduction of CD4+ cells at 14 days after UUO in both, ob/ob and db/db mice. In contrast, we could not detect significant differences in CD8+ cells and macrophage content. TGF- mRNA levels, TGF- induced Smad-2/3 activation and the upregulation of downstream target genes was significantly reduced in ob/ob mice. In addition we could demonstrate that leptin could enhance TGF- signaling in normal rat kidney fibroblasts in vitro. We conclude that leptin can serve as a cofactor of TGF- activation and thus, plays an important role in renal tubulointerstitial fibrosis. Therefore, selective blockade of the leptin axis might provide a therapeutic possibility to prevent or delay fibrotic kidney disease.