Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury
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 hemo...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1352 |
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| author | Laura E. Diepeveen Gaby Stegemann Erwin T. Wiegerinck Rian Roelofs Myrthe Naber Olivier Lóreal Bart Smeets Frank Thévenod Dorine W. Swinkels Rachel P. L. van Swelm |
| author_facet | Laura E. Diepeveen Gaby Stegemann Erwin T. Wiegerinck Rian Roelofs Myrthe Naber Olivier Lóreal Bart Smeets Frank Thévenod Dorine W. Swinkels Rachel P. L. van Swelm |
| author_sort | Laura E. Diepeveen |
| collection | DOAJ |
| description | 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<sub>cl1</sub>) cells with IL-6 or LPS did not induce <i>Hamp1</i> mRNA expression, whereas iron (FeS) and hemin significantly induced hepcidin synthesis (<i>p</i> < 0.05). Moreover, iron/heme-mediated hepcidin induction in mCCD<sub>cl1</sub> 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 (<i>p</i> < 0.001), NQO1 (<i>p</i> < 0.001), and TXNRD1 (<i>p</i> < 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 <i>Hamp1</i> 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 (<i>IL-6</i>, <i>TNFα</i>) but not <i>Hamp1</i>. However, since PHZ treatment also significantly reduced systemic hepcidin levels in both Wt and KO mice (both <i>p</i> < 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. |
| first_indexed | 2024-03-09T23:48:40Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:48:40Z |
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| spelling | doaj.art-5abcc355f0f84a1c9029593fc58c7c5a2023-11-23T16:39:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233135210.3390/ijms23031352Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney InjuryLaura E. Diepeveen0Gaby Stegemann1Erwin T. Wiegerinck2Rian Roelofs3Myrthe Naber4Olivier Lóreal5Bart Smeets6Frank Thévenod7Dorine W. Swinkels8Rachel P. L. van Swelm9Translational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsTranslational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsTranslational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsTranslational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsTranslational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsINSERM 1241, Nutrition, Metabolisms and Cancer (NuMeCan) Institute, University of Rennes, 35033 Rennes, FranceDepartment of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsInstitute of Physiology, Pathophysiology and Toxicology, Center for Biomedical Training and Research (ZBAF), University of Witten/Herdecke, 58455 Witten, GermanyTranslational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsTranslational Metabolic Laboratory (TML-830), Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsHemolysis 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<sub>cl1</sub>) cells with IL-6 or LPS did not induce <i>Hamp1</i> mRNA expression, whereas iron (FeS) and hemin significantly induced hepcidin synthesis (<i>p</i> < 0.05). Moreover, iron/heme-mediated hepcidin induction in mCCD<sub>cl1</sub> 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 (<i>p</i> < 0.001), NQO1 (<i>p</i> < 0.001), and TXNRD1 (<i>p</i> < 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 <i>Hamp1</i> 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 (<i>IL-6</i>, <i>TNFα</i>) but not <i>Hamp1</i>. However, since PHZ treatment also significantly reduced systemic hepcidin levels in both Wt and KO mice (both <i>p</i> < 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.https://www.mdpi.com/1422-0067/23/3/1352kidneyironhepcidinacute kidney injuryhemoglobin |
| spellingShingle | Laura E. Diepeveen Gaby Stegemann Erwin T. Wiegerinck Rian Roelofs Myrthe Naber Olivier Lóreal Bart Smeets Frank Thévenod Dorine W. Swinkels Rachel P. L. van Swelm Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury International Journal of Molecular Sciences kidney iron hepcidin acute kidney injury hemoglobin |
| title | Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury |
| title_full | Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury |
| title_fullStr | Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury |
| title_full_unstemmed | Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury |
| title_short | Investigating the Molecular Mechanisms of Renal Hepcidin Induction and Protection upon Hemoglobin-Induced Acute Kidney Injury |
| title_sort | investigating the molecular mechanisms of renal hepcidin induction and protection upon hemoglobin induced acute kidney injury |
| topic | kidney iron hepcidin acute kidney injury hemoglobin |
| url | https://www.mdpi.com/1422-0067/23/3/1352 |
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