Iron therapy mitigates chronic kidney disease progression by regulating intracellular iron status of kidney macrophages
Edwin Patino, Divya Bhatia, Steven Z. Vance, Ada Antypiuk, Rie Uni, Chantalle Campbell, Carlo G. Castillo, Shahd Jaouni, Francesca Vinchi, Mary E. Choi, Oleh Akchurin
Edwin Patino, Divya Bhatia, Steven Z. Vance, Ada Antypiuk, Rie Uni, Chantalle Campbell, Carlo G. Castillo, Shahd Jaouni, Francesca Vinchi, Mary E. Choi, Oleh Akchurin
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Research Article Nephrology

Iron therapy mitigates chronic kidney disease progression by regulating intracellular iron status of kidney macrophages

Abstract

Systemic iron metabolism is disrupted in chronic kidney disease (CKD). However, little is known about local kidney iron homeostasis and its role in kidney fibrosis. Kidney-specific effects of iron therapy in CKD also remain elusive. Here, we elucidate the role of macrophage iron status in kidney fibrosis and demonstrate that it is a potential therapeutic target. In CKD, kidney macrophages exhibited depletion of labile iron pool (LIP) and induction of transferrin receptor 1, indicating intracellular iron deficiency. Low LIP in kidney macrophages was associated with their defective antioxidant response and proinflammatory polarization. Repletion of LIP in kidney macrophages through knockout of ferritin heavy chain (Fth1) reduced oxidative stress and mitigated fibrosis. Similar to Fth1 knockout, iron dextran therapy, through replenishing macrophage LIP, reduced oxidative stress, decreased the production of proinflammatory cytokines, and alleviated kidney fibrosis. Interestingly, iron markedly decreased TGF-β expression and suppressed TGF-β–driven fibrotic response of macrophages. Iron dextran therapy and FtH suppression had an additive protective effect against fibrosis. Adoptive transfer of iron-loaded macrophages alleviated kidney fibrosis, validating the protective effect of iron-replete macrophages in CKD. Thus, targeting intracellular iron deficiency of kidney macrophages in CKD can serve as a therapeutic opportunity to mitigate disease progression.

Authors

Edwin Patino, Divya Bhatia, Steven Z. Vance, Ada Antypiuk, Rie Uni, Chantalle Campbell, Carlo G. Castillo, Shahd Jaouni, Francesca Vinchi, Mary E. Choi, Oleh Akchurin

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Figure 3

Iron dextran administration improves iron deficiency of kidney macrophages and reduces kidney macrophage oxidative stress and inflammation in mice with CKD.

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Iron dextran administration improves iron deficiency of kidney macrophag...
(A) Schematic diagram of iron dextran administration in mice with adenine-induced CKD and (B) Western blot analysis of FtH protein levels in kidney tissue of CKD mice in the absence (CKD) and presence (CKD+Fe) of iron administration; n = 3 per group. (C) Perls Prussian blue staining for ferric iron (scale bars: 3 mm for low magnification, 100 μm for high magnification) and transmission electron microscopy (original magnification, 5,000×, first 2 images, and 30,000×, last image) of kidney tissue of CKD mice in the absence and presence of iron administration. Arrows point at iron-loaded lysosomes within kidney macrophages (Mϕ). (D) Kidney tissue iron content in 2 groups of mice (n = 8–18 per group). (E) Iron therapy increases LIP and decreases TfR1 expression in CKD kidney macrophages, thus improving their iron deficiency status; n = 7–16 per group. (F) ROS and iNOS expression in CKD kidney macrophages in the absence and presence of iron therapy; n = 5–13 per group. (G) Iron therapy inhibits production of proinflammatory cytokines IL-6, IL-1β, and TNF-α in CKD kidney macrophages. (H) TGF-β expression in CKD kidney macrophages is suppressed by iron therapy. Dashed gray lines indicate mean values of the respective parameters in control mice (E–H). Error bars represent SEM. Data were analyzed using t test. *P < 0.05; **P < 0.01; ***P < 0.001.