Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside

Balla, József; Zarjou, Abolfazl

doi:10.3390/ijms22158174

Cited by 6 publications

(4 citation statements)

References 141 publications

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“…The induction of the HO-1/ferritin system has been shown to be protective in a number of injury models, including myocardial IR [ 33 , 34 ]. HO-1 expression is markedly induced in porcine myocardium following IR [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1

Machado

Spangler

Stacks

et al. 2022

IJMS

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Given the abundance of heme proteins (cytochromes) in the mitochondrion, it is evident that a meticulously orchestrated iron metabolism is essential for cardiac health. Here, we examined the functional significance of myocardial ferritin heavy chain (FtH) in a model of acute myocardial infarction. We report that FtH deletion did not alter either the mitochondrial regulatory and surveillance pathways (fission and fusion) or mitochondrial bioenergetics in response to injury. Furthermore, deletion of myocardial FtH did not affect cardiac function, assessed by measurement of left ventricular ejection fraction, on days 1, 7, and 21 post injury. To identify the modulated pathways providing cardiomyocyte protection coincident with FtH deletion, we performed unbiased transcriptomic analysis. We found that following injury, FtH deletion was associated with upregulation of several genes with anti-ferroptotic properties, including heme oxygenase-1 (HO-1) and the cystine/glutamate anti-porter (Slc7a11). These results suggested that HO-1 overexpression mitigates ferroptosis via upregulation of Slc7a11. Indeed, using transgenic mice with HO-1 overexpression, we demonstrate that overexpressed HO-1 is coupled with increased Slc7a11 expression. In conclusion, we demonstrate that following injury, myocardial FtH deletion leads to a compensatory upregulation in a number of anti-ferroptotic genes, including HO-1. Such HO-1 induction leads to overexpression of Slc7a11 and protects the heart against ischemia-reperfusion-mediated ferroptosis, preserves mitochondrial function, and overall function of the myocardium.

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Section: Discussionmentioning

confidence: 99%

Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1

Machado

Spangler

Stacks

et al. 2022

IJMS

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“…Destabilized intracellular HPs and attendant increased levels of free heme/Fe may thus provide one of the final common pathways for AKI, irrespective of the original insult. The following support this concept 1 : 1) Intracellular heme is generally elevated in AKI, and worsening of AKI occurs when heme degradation is compromised by impairment in or deficiency of heme oxygenase-1 or heme oxygenase-2 4, 9, 10 ; 2) free heme is damaging to the kidney and other organs and tissues (Table 2) 1,3,[11][12][13][14] ; and 3) heme, when used in large amounts to abort human porphyria, causes fulminant AKI 15 . Cellular egress and renal delivery.…”

Section: Overview Of Hp-based Processes That Injure the Kidneymentioning

confidence: 95%

Heme Proteins and Kidney Injury: Beyond Rhabdomyolysis

Nath¹,

Singh²,

Croatt³

et al. 2022

Kidney360

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Heme proteins, the stuff of life, represent an ingenious cellular strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the inherent risks to cellular vitality posed by unfettered and promiscuously reactive heme. Heme proteins, however, may be a double-edged sword as they can damage the kidney in certain settings. While such injury is often viewed mainly within the context of rhabdomyolysis and the nephrotoxicity of myoglobin, an increasing literature now attests to the fact that involvement of heme proteins in renal injury ranges well beyond the confines of this single disease (and its analogue, hemolysis); indeed, through the release of the defining heme motif, destabilization of intracellular heme proteins may be a common pathway for acute kidney injury, in general, and irrespective of the underlying insult. This brief review outlines current understanding regarding processes underlying such heme protein-induced acute kidney injury (AKI) and chronic kidney disease (CKD). Topics covered include, among others, the basis for renal injury following the exposure of the kidney to and its incorporation of myoglobin and hemoglobin; autooxidation of myoglobin and hemoglobin; destabilization of heme proteins and the release of heme; heme/iron/oxidant pathways of renal injury; generation of reactive oxygen species and reactive nitrogen species by NOX, iNOS, and myeloperoxidase; and the role of circulating cell-free hemoglobin in AKI and CKD. Also covered are the characteristics of the kidney that render this organ uniquely vulnerable to injury following myolysis and hemolysis, and pathobiologic effects emanating from free, labile heme. Mechanisms that defend against the toxicity of heme proteins are discussed, and the review concludes by outlining the therapeutic strategies that have arisen from current understanding of mechanisms of renal injury caused by heme proteins and how such mechanisms may be interrupted.

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“…28 The expression of HO-1 and ferritin co-occurs, and both are induced by iron and heme. 29 With the limitation of iron, nuclear receptor coactivator 4 (NOCA4) regulates the release of stored iron by conducting ferritin into lysosomes. 30 Labile iron without ferritin will be exported by transferrin (Tf), 31,32 which is located in serum and cytoplasm to maintain cellular homeostasis as well.…”

Section: Iron Transport and Homeostasismentioning

confidence: 99%

“…It acts as the major reservoir of labile iron to maintain iron homeostasis, making cells less susceptible to oxidative damage 28 . The expression of HO‐1 and ferritin co‐occurs, and both are induced by iron and heme 29 . With the limitation of iron, nuclear receptor coactivator 4 (NOCA4) regulates the release of stored iron by conducting ferritin into lysosomes 30 .…”

Section: Heme Metabolismmentioning

confidence: 99%

Heme metabolism and HO‐1 in the pathogenesis and potential intervention of endometriosis

Hou,

Lu,

Zhang

et al. 2024

American J Rep Immunol

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Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase‐1 (HO‐1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO‐1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti‐inflammatory, and anti‐proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

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Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside

Cited by 6 publications

References 141 publications

Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1

Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1

Heme Proteins and Kidney Injury: Beyond Rhabdomyolysis

Heme metabolism and HO‐1 in the pathogenesis and potential intervention of endometriosis

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