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.

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Skeletal muscle atrophy is caused by disruption in the homeostatic balance of muscle degeneration and regeneration under various pathophysiological conditions. We have previously reported that iron accumulation induces skeletal muscle atrophy via a ubiquitin ligase–dependent pathway. However, the potential effect of iron accumulation on muscle regeneration remains unclear. To examine the effect of iron accumulation on myogenesis, we used a mouse model with cardiotoxin (CTX)‐induced muscle regeneration in vivo and C2C12 mouse myoblast cells in vitro. In mice with iron overload, the skeletal muscles exhibited increased oxidative stress and decreased expression of satellite cell markers. Following CTX‐induced muscle injury, these mice also displayed delayed muscle regeneration with a decrease in the size of regenerating myofibers, reduced expression of myoblast differentiation markers, and decreased phosphorylation of MAPK signaling pathways. In vitro, iron overload also suppressed the differentiation of C2C12 myoblast cells but the suppression could be reversed by superoxide scavenging using tempol. Excess iron inhibits myogenesis via oxidative stress, leading to an imbalance in skeletal muscle homeostasis. —Ikeda, Y., Satoh, A., Horinouchi, Y., Hamano, H., Watanabe, H., Imao, M., Imanishi, M., Zamami, Y., Takechi, K., Izawa‐Ishizawa, Y., Miyamoto, L., Hirayama, T., Nagasawa, H., Ishizawa, K., Aihara, K.‐I., Tsuchiya, K., Tamaki, T. Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress. FASEB J. 33, 9551–9564 (2019). http://www.fasebj.org

Angiotensin II (ANG II) altered the expression of duodenal iron transporters and reduced hepcidin levels, contributing to the alteration of body iron distribution.

Ferritin (Ftn), an iron‐storage protein, is widely used as an indicator of body iron storage. Serum ferritin was upregulated under the inflammatory status. Recently, the secreted Ftn exerts certain biological actions, however, it remains unclear whether the secreted Ftn itself promotes inflammation. Here, we investigated the biological action of Ftn on inflammation. Murine peritoneal ascites‐derived macrophage, RAW264.7, was used in this study. Exogenous Ftn treatment as well as iron‐free Apo‐Ftn induced IL‐1ß expression and maturation in macrophage, resulting in increased IL‐1ß secretion in the supernatant. Ftn and Apo‐Ftn promoted caspase‐1 activation and upregulated the expression of nucleotide‐binding oligomerization domain (NOD)‐like receptor family, pyrin domain‐containing 3 (NLRP3), inflammasome activation. Ftn‐induced IL‐1ß activation and secretion were inhibited by caspase‐1 inhibitor or NLRP3 silencing. Ftn‐induced inflammasome activation was independent of iron content and inhibited by the pharmacological inhibition of nuclear factor kappa B (NF‐κB). Thus, the secreted Ftn possess proinflammatory activities to promote IL‐1ß production through the NF‐κB‐dependent transcriptional regulation of NLRP3‐inflammasome in macrophages, which is a novel finding of ferritin beyond the indicator of body iron content.