Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair

Ide, Shintaro; Ide, Kana; Abe, Koki; Kobayashi, Yoshihiko; Kitai, Hiroki; McKey, Jennifer; Strausser, Sarah A.; O’Brien, Lori L.; Tata, Aleksandra; Tata, Purushothama Rao; Souma, Tomokazu

doi:10.1016/j.celrep.2022.111610

Cited by 38 publications

(26 citation statements)

References 84 publications

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“…However, a potential role of Nrf2 in kidney repair has only been addressed very recently. In one study, the authors demonstrated that sex differences in resilience to ferroptotic cell death underlie the reduced kidney injury and enhanced repair of this organ in female vs. male mice [ 89 ]. Importantly, Nrf2 activation was identified as a female resilience mechanism against ferroptosis, and activation of Nrf2 in male mice protected proximal tubular cells from ferroptosis and improved cellular plasticity to the extent seen in female mice [ 89 ].…”

Section: Nrf2 In Repair Of Epithelial Tissuesmentioning

confidence: 99%

“…In one study, the authors demonstrated that sex differences in resilience to ferroptotic cell death underlie the reduced kidney injury and enhanced repair of this organ in female vs. male mice [ 89 ]. Importantly, Nrf2 activation was identified as a female resilience mechanism against ferroptosis, and activation of Nrf2 in male mice protected proximal tubular cells from ferroptosis and improved cellular plasticity to the extent seen in female mice [ 89 ]. Nrf2 activation may also promote repair following ischemia/reperfusion injury in the kidney, where Nrf2 activation is suppressed [ 90 ].…”

Section: Nrf2 In Repair Of Epithelial Tissuesmentioning

confidence: 99%

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Targeting NRF2 to promote epithelial repair

Hiebert

Werner

2023

Biochemical Society Transactions

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The transcription factor NRF2 is well known as a master regulator of the cellular stress response. As such, activation of NRF2 has gained widespread attention for its potential to prevent tissue injury, but also as a possible therapeutic approach to promote repair processes. While NRF2 activation affects most or even all cell types, its effect on epithelial cells during repair processes has been particularly well studied. In response to tissue injury, these cells proliferate, migrate and/or spread to effectively repair the damage. In this review, we discuss how NRF2 governs repair of epithelial tissues, and we highlight the increasing number of NRF2 targets with diverse roles in regulating epithelial repair.

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Section: Nrf2 In Repair Of Epithelial Tissuesmentioning

confidence: 99%

Section: Nrf2 In Repair Of Epithelial Tissuesmentioning

confidence: 99%

Targeting NRF2 to promote epithelial repair

Hiebert

Werner

2023

Biochemical Society Transactions

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“…Importantly, in a recent study on renal sex differences in kidney injury and repair, Gsta4 and Cbr1 were identi ed as female-enriched resilience genes against ferroptosis downstream of Nrf2 activation [22]. Another Nrf2 target gene that becomes upregulated upon cellular stress is Abcc3 [5], which we found to be enriched in female tubules.…”

Section: Discussionmentioning

confidence: 74%

Renal microdissection revisited: Lectin-aided sorting of intact tubular nephron segments as a new tool to study sex-related differences in kidney disease

Roskosch

Uldry

Huynh‐Do

et al. 2023

Preprint

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In our aging society an increasing prevalence of chronic kidney disease (CKD) meets a general shortage of organ donors. As the economic burden of CKD is increasing, kidney research made significant progress in the early detection, repair, or replacement of damaged renal tissue, taking in consideration sex-related differences, and precision medicine principles. Despite recent advancements in renal organoid research, the generation of fully functional nephrons in-vitro is so far not achievable. Here we describe a novel lectin-guided protocol to sort renal tissue into four pure, functionally diverse nephron segments with high yield and intact 3D tubular morphology. We validated tissue-sorted fragments with proximal or distal convoluted tubular identity using bottom-up proteomics and assessed sex-related differences. Compared to males, females showed higher abundance of proteins involved in metabolism and excretion of xenobiotics, as well as in cell cycle progression or proliferation, which together might enhance their ability to better cope with renal injury. The major advantage of our protocol – high yield of sorted nephron segments with preserved 3D structure – will allow us to reconstruct miniature kidneys ex-vivo, by combining it with cutting-edge bio-printing techniques. Besides large-scale drug screening or the identification of segment specific biomarkers in renal disease, they could pave the way to generate functional renal replacement units for regenerative medicine. Furthermore, if applied to human biopsies, our method could improve patient-specific renal disease assessment. In conclusion, our method represents a cost-efficient and broadly applicable tool with the potential to propel personalized regenerative kidney research.

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“…Ferroptosis, as a newly discovered RCD, has attracted the attention of the scientific community. Increasing evidence links ferroptosis to the occurrence and development of various diseases. − Therefore, it is urgent to develop inhibitors and inducers of ferroptosis with therapeutic value. Here, we described the core molecular mechanisms of ferroptosis, such as iron metabolism, lipid metabolism, cyst(e)ine-GSH-GPX4 axis, FSP1-CoQH 2 axis, and GCH1-BH 4 axis.…”

Section: Future Perspectivementioning

confidence: 99%

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

Zhou

Zhang

2023

J. Agric. Food Chem.

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Flavonoids are a class of bioactive phytochemicals containing a core 2-phenylchromone skeleton and are widely found in fruits, vegetables, and herbs. Such natural compounds have gained significant attention due to their various health benefits. Ferroptosis is a recently discovered unique iron-dependent mode of cell death. Unlike traditional regulated cell death (RCD), ferroptosis is associated with excessive lipid peroxidation on cellular membranes. Accumulating evidence suggests that this form of RCD is involved in a variety of physiological and pathological processes. Notably, multiple flavonoids have been shown to be effective in preventing and treating diverse human diseases by regulating ferroptosis. In this review, we introduce the key molecular mechanisms of ferroptosis, including iron metabolism, lipid metabolism, and several major antioxidant systems. Additionally, we summarize the promising flavonoids targeting ferroptosis, which provides novel ideas for the management of diseases such as cancer, acute liver injury, neurodegenerative diseases, and ischemia/reperfusion (I/R) injury.

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Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair

Cited by 38 publications

References 84 publications

Targeting NRF2 to promote epithelial repair

Targeting NRF2 to promote epithelial repair

Renal microdissection revisited: Lectin-aided sorting of intact tubular nephron segments as a new tool to study sex-related differences in kidney disease

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

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