Leptin is a coactivator of TGF-beta in unilateral ureteral obstructive kidney disease.
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)-beta mRNA levels, TGF-beta-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-beta signaling in normal rat kidney fibroblasts in vitro. We conclude that leptin can serve as a cofactor of TGF-beta 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.
Department of Nephrology, Hannover Medical School, Hannover, Germany.
Philipp
P
Kümpers
Faikah
F
Gueler
Song
S
Rong
Michael
M
Mengel
Irini
I
Tossidou
Imke
I
Peters
Hermann
H
Haller
Mario
M
Schiffer
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009395:Nephritis, Interstitial / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications / Q000378:metabolism*
D020738:Leptin; D054411:Receptors, Leptin; D016212:Transforming Growth Factor beta