Heme Oxygenase-1 in Kidney Health and Disease

Lever, Jeremie M.; Boddu, Ravindra; George, James F.; Agarwal, Anupam

doi:10.1089/ars.2016.6659

Cited by 116 publications

(102 citation statements)

References 166 publications

(211 reference statements)

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“…Within the kidney, HO1 is expressed following injury to the proximal tubules, glomeruli, or interstitial cells and is upregulated in renal mononuclear phagocytes in response to injury 85 . One study showed that levels of plasma and urinary HO1 are significantly higher in rats and humans with AKI than in healthy controls, although sample sizes used in that study were smaller than those of studies that have validated the specificity of other novel biomarkers, such as the 2008 and 2010 studies validating the performance of KIM1 77,78,86 .…”

Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

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Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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“…There are several excellent reviews that discuss the cytoprotective nature of HO-1 in kidney physiology and disease states. 15–19 The elegant review by Courtney and colleagues discussed the role of HO-1 in mediating protection during kidney diseases, with emphasis on transplantation. 15 The focus of this current review is to highlight key aspects of the mechanisms by which HO-1 confers protection during AKI, and to discuss the most recent translational advances in this field.…”

Section: Case Vignettementioning

confidence: 99%

“…Second, HO-1 gene expression is regulated differently in mice and humans 104, 105 . These dissimilarities include contrasting responses to various stimuli such as hypoxia, heat shock, hyperosmolarity, and cytokines such as interferon γ .…”

Section: Recent Advancesmentioning

confidence: 99%

“…In addition, the molecular mechanisms of human HO-1 gene regulation by an intronic enhancer that facilitates HO-1 gene expression via chromatin looping have not been shown in the rodent HO-1 genes. 104, 105 These limitations prompted generation of a novel “humanized” transgenic mouse model, consisting of the human HO-1 gene in addition to its regulatory regions on a HO-1 −/− background. 77 This study confirmed rescue of the pathologic phenotypes observed in HO-1 −/− mice via functional presence of the human HO-1 gene (Figure 3).…”

Section: Recent Advancesmentioning

confidence: 99%

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Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury

Bolisetty

Zarjou

Agarwal

2017

American Journal of Kidney Diseases

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122

114

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A common clinical condition, acute kidney injury (AKI) significantly influences morbidity and mortality, particularly in critically ill patients. The pathophysiology of AKI is complex and involves multiple pathways including inflammation, autophagy, cell cycle progression, and oxidative stress. Recent evidence suggests that a single insult to the kidney significantly enhances the propensity to develop chronic kidney disease. Therefore, generation of effective therapies against AKI are timely. In this context, the cytoprotective effects of heme oxygenase 1 (HO-1) in animal models of AKI are well documented. HO-1 modulates oxidative stress, autophagy, and inflammation, and regulates the progression of cell cycle via direct and indirect mechanisms. These beneficial effects of HO-1 induction during AKI are, in part, mediated by the by-products of the HO reaction (iron, carbon monoxide, and bile pigments). This review highlights the recent advances in the molecular mechanisms of HO-1–mediated cytoprotection and discusses the translational potential of HO-1 induction in AKI.

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“…HO is a key molecule in heme degradation, leading to the generation of biliverdin. Biliverdin is then reduced to bilirubin by biliverdin reductase [28,29]. Thus, increased EPO production may be associated with elevated bilirubin via the hypoxic stress pathway involving hypoxia inducible factor-1α and HO, which could explain that we observed an association between bilirubin and EPO but not transaminases in this study ( Fig.…”

Section: Discussionmentioning

confidence: 62%

Endogenous Erythropoietin and Hepatic Dysfunction in Acute Kidney Injury Requiring Renal Replacement Therapy

Matsuura

Doi

Komaru

et al. 2019

Nephron

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Backgrounds/Objectives: Elevated erythropoietin (EPO) is observed in human acute kidney injury (AKI). Whether blood EPO level is associated with mortality or other organ dysfunction in critically ill patients is unknown. Methods: A prospective observational cohort study of 162 AKI patients requiring renal replacement therapy (RRT) was conducted in our intensive care unit (ICU) during October 2013 through October 2016. We evaluated the relation with plasma EPO at RRT initiation and 90-day mortality, hemoglobin, urine output, and sequential organ failure assessment (SOFA) score until day 7 or discharge from the ICU. Results: The analysis revealed that EPO was significantly associated with 90-day mortality with an adjusted hazard ratio of 2.13 (95% CI 1.11–5.78). Hemoglobin levels, RRT dependence, and daily urine output on days 1 through 7 did not differ between the high EPO group (≥56.2 mIU/mL) and low EPO groups (< 56.2 mIU/mL). As for organ dysfunction, hyperbilirubinemia patients (≥2.0 mg/dL; hepatic SOFA ≥2) were more frequent in the high EPO group (62.1 vs. 37.9%; p < 0.05), while other SOFA scores did not differ between both groups. Exacerbation of hepatic dysfunction was observed more frequently in the high EPO than the low EPO group (49.3 vs. 27.2%; p < 0.05). Conclusion: Elevated EPO was not associated with anemia or RRT dependence. However, higher rates of mortality and hepatic dysfunction were observed in high EPO patients than in low EPO patients.

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Heme Oxygenase-1 in Kidney Health and Disease

Cited by 116 publications

References 166 publications

Advances in predictive in vitro models of drug-induced nephrotoxicity

Advances in predictive in vitro models of drug-induced nephrotoxicity

Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury

Endogenous Erythropoietin and Hepatic Dysfunction in Acute Kidney Injury Requiring Renal Replacement Therapy

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