Heme Oxygenase-1 Gene Polymorphisms—Toward Precision Medicine for AKI

Curtis, Lisa M.; Agarwal, Anupam

doi:10.1681/asn.2016060699

Cited by 2 publications

(1 citation statement)

References 21 publications

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“…31). In addition, recent studies have linked genetic polymorphisms in the human HO-1 gene to the development of AKI in cardiac surgery patients (6,23). Similarly, differential expression of genes, which modulate cellular iron content and iron homeostasis, has been demonstrated to regulate ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells

Adedoyin

Boddu

Traylor

et al. 2018

American Journal of Physiology-Renal Physiology

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297

192

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Ferroptosis is an iron-dependent form of regulated nonapoptotic cell death, which contributes to damage in models of acute kidney injury (AKI). Heme oxygenase-1 (HO-1) is a cytoprotective enzyme induced in response to cellular stress, and is protective against AKI because of its antiapoptotic and anti-inflammatory properties. However, the role of HO-1 in regulating ferroptosis is unclear. The purpose of this study was to elucidate the role of HO-1 in regulating ferroptotic cell death in renal proximal tubule cells (PTCs). Immortalized PTCs obtained from HO-1 and HO-1 mice were treated with erastin or RSL3, ferroptosis inducers, in the presence or absence of antioxidants, an iron source, or an iron chelator. Cells were assessed for changes in morphology and metabolic activity as an indicator of cell viability. Treatment of HO-1 PTCs with erastin resulted in a time- and dose-dependent increase in HO-1 gene expression and protein levels compared with vehicle-treated controls. HO-1 cells showed increased dose-dependent erastin- or RSL3-induced cell death in comparison to HO-1 PTCs. Iron supplementation with ferric ammonium citrate in erastin-treated cells decreased cell viability further in HO-1 PTCs compared with HO-1 cells. Cotreatment with ferrostatin-1 (ferroptosis inhibitor), deferoxamine (iron chelator), or N-acetyl-l-cysteine (glutathione replenisher) significantly increased cell viability and attenuated erastin-induced ferroptosis in both HO-1 and HO-1 PTCs. These results demonstrate an important antiferroptotic role of HO-1 in renal epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells

Adedoyin

Boddu

Traylor

et al. 2018

American Journal of Physiology-Renal Physiology

Self Cite

297

192

View full text Add to dashboard Cite

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Unique sex- and age-dependent effects in protective pathways in acute kidney injury

Boddu

Fan

Rangarajan

et al. 2017

American Journal of Physiology-Renal Physiology

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Sex and age influence susceptibility to acute kidney injury (AKI), with young females exhibiting lowest incidence. In these studies, we investigated mechanisms which may underlie the sex/age-based dissimilarities. Cisplatin (Cp)-induced AKI resulted in morphological evidence of injury in all groups. A minimal rise in plasma creatinine (PCr) was seen in Young Females, whereas in Aged Females, PCr rose precipitously. Relative to Young Males, Aged Males showed significantly, but temporally, comparably elevated PCr. Notably, Aged Females showed significantly greater mortality, whereas Young Females exhibited none. Tissue KIM-1 and plasma NGAL were significantly lower in Young Females than all others. IGFBP7 levels were modestly increased in both Young groups. IGFBP7 levels in Aged Females were significantly elevated at baseline relative to Aged Males, and increased linearly through , when these levels were comparable in both Aged groups. Plasma cytokine levels similarly showed a pattern of protective effects preferentially in Young Females. Expression of the drug transporter MATE2 did not explain the sex/age distinctions. Heme oxygenase-1 (HO-1) levels (~28-kDa species) showed elevation at in all groups with highest levels seen in Young Males. Exclusively in Young Females, these levels returned to baseline on , suggestive of a more efficient recovery. In aggregate, we demonstrate, for the first time, a distinctive pattern of response to AKI in Young Females relative to males which appears to be significantly altered in aging. These distinctions may offer novel targets to exploit therapeutically in both females and males in the treatment of AKI.

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Heme Oxygenase-1 Gene Polymorphisms—Toward Precision Medicine for AKI

Cited by 2 publications

References 21 publications

Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells

Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells

Unique sex- and age-dependent effects in protective pathways in acute kidney injury

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