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 p22phox 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.

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis

“…In keeping with our studies, iron reduction by DFO was found to be effective in mitigating macrophage infiltration, inflammatory cytokines, and adiposity in KKAy mice . DFO was also effective in ameliorating fibrosis in a mouse model of chronic kidney disease . Although these studies and our observations point to the beneficial effects of iron reduction in patients with NAFLD, more studies need to be performed before it is commonly accepted …”

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

“…In addition, while this manuscript was in preparation, it was reported that iron chelation with deferoxamine alleviated renal interstitial fibrosis in mice with unilateral ureteral obstruction. 27 About the difference between dietary iron restriction and iron chelation by the drugs to reduce iron accumulation in the kidney, the effect of dietary iron restriction is to prevent further iron accumulation in the kidney, while that of iron chelation by the drugs is to deprive iron accumulation in the kidney.…”

Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology

“…Similar to animal studies, greater suppression of hepcidin in human patients with kidney failure is advantageous in treating renal anemia through correction of iron availability . On the other hand, previous studies have already shown that iron chelation does prevent progression of kidney function in animal models, while results from human studies show that the use of these therapeutic agents ameliorates iron dysmetabolism in renal anemia . But, the use of these agents in humans poses some questions about their safety profile, which makes the case for new therapeutic agents .…”