Heme oxygenase-1 and acute kidney injury

Nath, Karl A.

doi:10.1097/01.mnh.0000437613.88158.d3

Cited by 110 publications

(135 citation statements)

References 59 publications

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“…21,22 HO-1 is ubiquitously expressed in unstressed cells at low levels but is highly induced in response to cell injury mediated by oxidative or proinflammatory stress, heavy metals, ischemia and hypoxia. 23,24 Its cytoprotective and anti-apoptotic properties are mediated by degradation of the pro-oxidant heme into iron, biliverdin and carbon monoxide via induction of p38 MAPK and PI3K/Akt signal transduction pathways. 25 In contrast, pronounced chemical or genetic inhibition of basal HO-1 levels is associated with increased cell death and tissue necrosis in models of Alzheimer's disease and aging.…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

102

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Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality and morbidity, but there is no high throughput in vitro method for predictive nephrotoxicity assessment. We show that primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated epithelial cells rendering them desirable to use in such in vitro systems. To identify a reliable biomarker of nephrotoxicity, we conducted multiplexed gene expression profiling of HPTECs after exposure to six different concentrations of nine human nephrotoxicants. Only overexpression of the gene encoding heme oxygenase-1 (HO-1) significantly correlated with increasing dose for six of the compounds, and significant HO-1 protein deregulation was confirmed with each of the nine nephrotoxicants. Translatability of HO-1 increase across species and platforms was demonstrated by computationally mining two large rat toxicogenomic databases for kidney tubular toxicity and by observing a significant increase in HO-1 after toxicity using an ex vivo three-dimensional microphysiologic system (kidneyon-a-chip). The predictive potential of HO-1 was tested using an additional panel of 39 mechanistically distinct nephrotoxic compounds. Although HO-1 performed better (area under the curve receiver-operator characteristic curve [AUC-ROC]=0.89) than traditional endpoints of cell viability (AUC-ROC for ATP=0.78; AUC-ROC for cell count=0.88), the combination of HO-1 and cell count further improved the predictive ability (AUC-ROC=0.92). We also developed and optimized a homogenous time-resolved fluorescence assay to allow high throughput quantitative screening of nephrotoxic compounds using HO-1 as a sensitive biomarker. This cell-based approach may facilitate rapid assessment of potential nephrotoxic therapeutics and environmental chemicals. Drugs and environmental chemicals, such as aminoglycoside antibiotics, analgesics, chemotherapeutic agents, and heavy metals, as well as endemic toxins like aristolochic acid are a common cause of AKI or CKD. 1,2 Current approaches to conduct safety and risk assessment of compounds rely predominantly on animal studies, and these results are extrapolated to dose effects in humans despite knowledge that the typical responses of animal models and humans can differ greatly. 3 The lack of adequate models to accurately predict human toxicity contributes to an underestimation of the kidney toxic potential of new therapeutic candidates, which also explains why nephrotoxic effects in patients are often only detected during late phase

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Section: Discussionmentioning

confidence: 99%

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

102

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“…In spite of the relatively big size of glomerular endothelial its proinflammatory effects, as inducing the chemokines such as monocyte chemoattractant protein-1 throughout the redox-sensitive transcription factor NF-KB [15] . The heme group of haemoglobin may also decrease nitric oxide availability, promoting intrarenal vasoconstriction and ischemia [19] .…”

Section: Glomerular Endothelial Cell and Surface Layer Injuriesmentioning

confidence: 99%

“…Hb under the epithelial cell oxidant conditions dissociates into heme and globin. Heme oxigenase-1 (HO-1) catalyzes the conversion of heme to biliverdin, iron and carbon monoxide [15] . At that time, the bilirubin reductase converts biliverdin in bilirubin and the iron is stored as Ferritin (Figure 1).…”

Section: Haematuriamentioning

confidence: 99%

Pathogenesis of glomerular haematuria

Yuste

Gutiérrez

Sevillano

et al. 2015

WJN

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Haematuria was known as a benign hallmark of some glomerular diseases, but over the last decade, new evidences pointed its negative implications on kidney disease progression. Cytotoxic effects of oxidative stress induced by hemoglobin, heme, or iron released from red blood cells may account for the tubular injury observed in human biopsy specimens. However, the precise mechanisms responsible for haematuria remain unclear. The presence of red blood cells (RBCs) with irregular contours and shape in the urine indicates RBCs egression from the glomerular capillary into the urinary space. Therefore glomerular haematuria may be a marker of glomerular filtration barrier dysfunction or damage. In this review we describe some key issues regarding epidemiology and pathogenesis of haematuric diseases as well as their renal morphological findings.

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“…9 This finding is in line with the renal-protective and antiinflammatory role attributed to HO-1 in IRI. 7,15 Strikingly, at the same time, there was a dramatic reduction in the number and proportion of renal DCs after ischemia in the HO-1 KO mice. 9 DCs are known to traffick from the postischemic kidney to the renal draining lymph node where they present antigens to T cells, 17 and enhanced trafficking could explain the reduction in renal DCs observed in HO-1-deficient mice.…”

mentioning

confidence: 95%

“…6 These findings demonstrate that HO-1 can have disparate functions depending on the cell type and nature of the pathology being studied. A protective role for HO-1 in AKI models including kidney ischemia reperfusion injury (IRI), cisplatin nephrotoxicity, and others has been recognized for many years (see Nath 7 and references therein). HO-1 expression is induced quickly in the kidney during injury and HO-1 activity serves to limit renal injury and dysfunction.…”

mentioning

confidence: 99%