title: Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.
abstract: Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22(phox) expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses.
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan ; Student Lab, The University of Tokushima Faculty of Medicine, Tokushima, Japan.
authors.forename: Iori
authors.initials: I
authors.lastname: Ozono
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Tajima
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Imao
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Horinouchi
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Izawa-Ishizawa
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kihira
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Licht
authors.initials: L
authors.lastname: Miyamoto
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015913:Chelation Therapy / Q000379:methods*; D003676:Deferoxamine / Q000494:pharmacology*; D005355:Fibrosis; D007150:Immunohistochemistry; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: D007502:Iron Chelating Agents; D016212:Transforming Growth Factor beta; D003676:Deferoxamine