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ORIGINAL RESEARCH article

Front. Physiol.
Sec. Renal Physiology and Pathophysiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1430946

Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage

Provisionally accepted
Mira Hanna Mira Hanna 1*Ahmed Akabawy Ahmed Akabawy 2Mohamed Mansour Khalifa Mohamed Mansour Khalifa 3,4Marawan Abd Elbaset Marawan Abd Elbaset 5Reda Abdelnasser Imam Reda Abdelnasser Imam 6Hanan Seddiek Hanan Seddiek 3
  • 1 Department of Medical Physiology,, Kasr Al Ainy Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt
  • 2 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt, Cairo, Egypt
  • 3 Department of Medical Physiology, Kasr Al Ainy Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt
  • 4 Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
  • 5 Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt, cairo, Egypt
  • 6 Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Beni Suef, Egypt

The final, formatted version of the article will be published soon.

    Sepsis, the most common cause of acute kidney injury, remains a major socioeconomic burden. A dysregulated immune response leads to progressive organ dysfunction. Although numerous inflammatory pathways were described, a lot is still vague and needs to be studied in terms of the mechanisms to improve therapeutic intervention. We tackled the relationship between intracellular iron overload and macrophage polarization within 6, 24, and 72 hrs of sepsis induction. In our study, sepsis-induced kidney injury was performed using the cecal ligation and puncture ( CLP) model. Our results showed severe renal tissue damage with a progressive increase in serum BUN and creatinine with architectural tissue damage and positive PAS staining. There was increased expression of CD8 + CD68 + M1 macrophage markers with upregulation of iNOS and co-expression of CD163 + . Alternatively, Arg1 + Fizz1 + M2 macrophage markers were downregulated with increased iNOS/Arg1 ratio. TFR1, Cubilin, and DMT1, as iron transport systems, were increased compared to sham but were significant after 72 hrs, while ZIP8 showed no significant change. There was a correlation between iron overload and M1 macrophage polarization with CD163 + phenotype, together with fibrotic changes. The intracellular iron overload with downregulation of ferritin was strongly related to macrophage polarization that was exaggerated at 72 hrs. Finally, early introduced therapy to target free iron during sepsis might be a suggested novel solution for protecting the renal tissue from acute injury due to macrophage activation that may end up with chronic kidney injury if not mortality.

    Keywords: Sepsis, Acute Kidney Injury, Macrophage polarization, iron homeostasis, Macrophage markers, Iron transporters

    Received: 10 May 2024; Accepted: 06 Jan 2025.

    Copyright: © 2025 Hanna, Akabawy, Khalifa, Elbaset, Imam and Seddiek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Mira Hanna, Department of Medical Physiology,, Kasr Al Ainy Hospital, Faculty of Medicine, Cairo University, Cairo, Egypt

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