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Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury. | LitMetric

Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury.

Int J Mol Sci

Translational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Published: January 2022

AI Article Synopsis

  • Hemolysis can lead to acute kidney injury (AKI), with the hormone hepcidin potentially protecting the kidneys in this context.
  • In experiments with mouse kidney cells, iron and hemin were found to significantly stimulate hepcidin production, while inflammation-related factors like IL-6 or LPS did not.
  • The study highlighted that kidney hepcidin regulation is primarily driven by iron rather than inflammation, revealing complex interactions of iron regulation in both local kidney responses and broader systemic effects during AKI.

Article Abstract

Hemolysis is known to cause acute kidney injury (AKI). The iron regulatory hormone hepcidin, produced by renal distal tubules, is suggested to exert a renoprotective role during this pathology. We aimed to elucidate the molecular mechanisms of renal hepcidin synthesis and its protection against hemoglobin-induced AKI. In contrast to known hepatic hepcidin induction, incubation of mouse cortical collecting duct (mCCD) cells with IL-6 or LPS did not induce mRNA expression, whereas iron (FeS) and hemin significantly induced hepcidin synthesis ( < 0.05). Moreover, iron/heme-mediated hepcidin induction in mCCD cells was caused by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, as indicated by increased nuclear Nrf2 translocation and induced expression of Nrf2 downstream targets GCLM ( < 0.001), NQO1 ( < 0.001), and TXNRD1 ( < 0.005), which could be prevented by the known Nrf2 inhibitor trigonelline. Newly created inducible kidney-specific hepcidin KO mice demonstrated a significant reduction in renal mRNA expression. Phenylhydrazine (PHZ)-induced hemolysis caused renal iron loading and oxidative stress in both wildtype (Wt) and KO mice. PHZ treatment in Wt induced inflammatory markers (, ) but not . However, since PHZ treatment also significantly reduced systemic hepcidin levels in both Wt and KO mice (both < 0.001), a dissection between the roles of systemic and renal hepcidin could not be made. Combined, the results of our study indicate that there are kidney-specific mechanisms in hepcidin regulation, as indicated by the dominant role of iron and not inflammation as an inducer of renal hepcidin, but also emphasize the complex interplay of various iron regulatory mechanisms during AKI on a local and systemic level.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835743PMC
http://dx.doi.org/10.3390/ijms23031352DOI Listing

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