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Leptin is a coactivator of TGF- in unilateral ureteral obstructive kidney disease

¹Department of Nephrology and ²Institute of Pathology, Hannover Medical School, Hannover, Germany

Submitted 3 January 2007 ; accepted in final form 7 August 2007

Progressive tubulointerstitial fibrosis is the common end point leading to end-stage renal disease in experimental and clinical settings. Since the peptide hormone leptin is involved not only 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 tubulointerstitial 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 with that in sham-operated mice by performing immunohistochemistry, quantitative PCR, and Western blotting. We found that tubulointerstitial fibrosis was significantly reduced in the obstructed kidneys of ob/ob compared with 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. Transforming growth factor (TGF)- mRNA levels, TGF--induced Smad-2/3 activation, and the upregulation of downstream target genes were significantly reduced in ob/ob mice. In addition, we demonstrated 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.

tubulointerstitial fibrosis; inflammation; transforming growth factor-; obesity