Renoprotective Potency of Heme Oxygenase-1 Induction in Rat Renal Ischemia-Reperfusion

Chok, Mohammed Koussai; Ferlicot, Sophie; Conti, Marc; Almolki, Abdelhamid; Dürrbach, Antoine; Loric, Sylvain; Galand, Benoît; Droupy, S.; Eschwège, P.

doi:10.2174/187152809789352186

Cited by 28 publications

(28 citation statements)

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“…In comparison, the single-pathway renoprotectant hemin was used as a reference drug. A previous study demonstrated hemin as a renoprotectant against ischemic renal injuries [22]. We confirmed that both curcumin and hemin, at the same concentration of 10 µM, could relieve oxidative stress induced in glomerular mesangial cells by H 2 O 2 treatment (Figure 4).…”

Section: Resultssupporting

confidence: 84%

The Use of Functional Chemical-Protein Associations to Identify Multi-Pathway Renoprotectants

Meng

Zhang

et al. 2014

PLoS ONE

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Typically, most nephropathies can be categorized as complex human diseases in which the cumulative effect of multiple minor genes, combined with environmental and lifestyle factors, determines the disease phenotype. Thus, multi-target drugs would be more likely to facilitate comprehensive renoprotection than single-target agents. In this study, functional chemical-protein association analysis was performed to retrieve multi-target drugs of high pathway wideness from the STITCH 3.1 database. Pathway wideness of a drug evaluated the efficiency of regulation of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in quantity. We identified nine experimentally validated renoprotectants that exerted remarkable impact on KEGG pathways by targeting a limited number of proteins. We selected curcumin as an illustrative compound to display the advantage of multi-pathway drugs on renoprotection. We compared curcumin with hemin, an agonist of heme oxygenase-1 (HO-1), which significantly affects only one KEGG pathway, porphyrin and chlorophyll metabolism (adjusted p = 1.5×10−5). At the same concentration (10 µM), both curcumin and hemin equivalently mitigated oxidative stress in H2O2-treated glomerular mesangial cells. The benefit of using hemin was derived from its agonistic effect on HO-1, providing relief from oxidative stress. Selective inhibition of HO-1 completely blocked the action of hemin but not that of curcumin, suggesting simultaneous multi-pathway intervention by curcumin. Curcumin also increased cellular autophagy levels, enhancing its protective effect; however, hemin had no effects. Based on the fact that the dysregulation of multiple pathways is implicated in the etiology of complex diseases, we proposed a feasible method for identifying multi-pathway drugs from compounds with validated targets. Our efforts will help identify multi-pathway agents capable of providing comprehensive protection against renal injuries.

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Section: Resultssupporting

confidence: 84%

The Use of Functional Chemical-Protein Associations to Identify Multi-Pathway Renoprotectants

Meng

Zhang

et al. 2014

PLoS ONE

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“…are routinely employed, without any reports of nephrotoxicity. Conversely, such doses have actually protected rodent kidneys from a variety of acute insults (Chok et al, 2009; Kang et al, 2013; Kim et al, 2006), while slowing or preventing loss of function in chronic renal failure models (Desbuards et al, 2009; Jadhav et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Systemic hemin therapy attenuates blood–brain barrier disruption after intracerebral hemorrhage

Chen-Roetling

Regan

2014

Neurobiology of Disease

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Injury to the blood-brain barrier (BBB) is a key feature of intracerebral hemorrhage (ICH) and may contribute to perihematomal cell injury. Pretreatment with the heme oxygenase (HO)-1 inducer hemin improves barrier function and neurological outcome in experimental models of traumatic and ischemic CNS injury. Since hemin is already in clinical use to treat acute porphyrias, this translational study was designed to test its effect on BBB function when initiated after ICH in two mouse models. At a dose similar to those used in most preconditioning studies (26 mg/kg i.p.), post-hemorrhage treatment with hemin reduced parenchymal extravasation of Evans blue by about three-quarters in both the blood injection and collagenase ICH models. Similar efficacy was observed when treatment was begun at one or three hours. At the lower dose that is currently in clinical use (4 mg/kg beginning at 3 hours), hemin also improved barrier function in both models, as assessed by both Evans blue and FITC-dextran leakage; however, it was somewhat less potent, reducing Evans blue leakage by about half. This dose was nevertheless sufficient to attenuate striatal cell loss and accelerate neurological recovery. Consistent with prior observations, striatal HO-1 expression was increased by hemin, and was localized to perivascular cells. These results suggest that hemin may be an effective therapy for ICH with a clinically relevant time window. Further study of the repurposing of this old drug seems warranted.

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“…JNK activation is associated with cell death, and ERK activity is considered protective (105). Other candidate mediators of preconditioning include heat shock proteins (HSP27, HSP70) (131,140), heme oxygenase (141,142), reactive oxygen species (143), and endoplasmic reticulum stress proteins (144). Tregs have also been implicated in protection, since transfer of these cells from a preconditioned mouse to a normal mouse protected the recipient against subsequent IRI (145)(146)(147).…”

Section: Protection Against Injury By Ischemic Preconditioningmentioning

confidence: 99%

Cellular pathophysiology of ischemic acute kidney injury

Bonventre¹,

Yang²

2011

J. Clin. Invest.

1,601

1,604

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Renoprotective Potency of Heme Oxygenase-1 Induction in Rat Renal Ischemia-Reperfusion

Abstract: HO-1 decreased the degree and severity of tubular damage after IR, probably by attenuating the cytotoxic effects of inflammatory infiltrates and apoptosis.

Cited by 28 publications

References 0 publications

The Use of Functional Chemical-Protein Associations to Identify Multi-Pathway Renoprotectants

The Use of Functional Chemical-Protein Associations to Identify Multi-Pathway Renoprotectants

Systemic hemin therapy attenuates blood–brain barrier disruption after intracerebral hemorrhage

Cellular pathophysiology of ischemic acute kidney injury

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