Heme Oxygenase 1 Modulates Thrombomodulin and Endothelial Protein C Receptor Levels to Attenuate Septic Kidney Injury

Kang, Kai; Nan, Chuanchuan; Fei, Dongsheng; Meng, Xianglin; Li, Wen; Zhang, Weiwei; Jiang, Lei; Zhao, Mingran; Pan, Shangha; Zhao, Mingyan

doi:10.1097/shk.0b013e31829d23f5

Cited by 26 publications

(23 citation statements)

References 29 publications

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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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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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Section: Heme Oxygenase-1 and Sepsis-associated Thrombotic Microangiomentioning

confidence: 99%

“…Recent studies demonstrate the protective effects of HO-1 in thrombotic microangiopathy (TMA)-associated AKI that occurs in sepsis induced by cecal ligation and puncture [32 ▪ ]. This sepsis model fosters a procoagulant state, diminishes plasma levels of activated protein C (APC), and decreases renal expression of thrombomodulin and endothelial protein C receptor (EPCR) [32 ▪ ]. Pretreatment with hemin augments glomerular HO-1 expression and renal expression of thrombomodulin and EPCR, while reducing renal dysfunction, glomerular TMA, and the procoagulant state; hemin also increases plasma levels of APC in this model [32 ▪ ].…”

Section: Heme Oxygenase-1 and Sepsis-associated Thrombotic Microangiomentioning

confidence: 99%

“…This sepsis model fosters a procoagulant state, diminishes plasma levels of activated protein C (APC), and decreases renal expression of thrombomodulin and endothelial protein C receptor (EPCR) [32 ▪ ]. Pretreatment with hemin augments glomerular HO-1 expression and renal expression of thrombomodulin and EPCR, while reducing renal dysfunction, glomerular TMA, and the procoagulant state; hemin also increases plasma levels of APC in this model [32 ▪ ]. These effects of hemin, coupled with the converse effects when heme oxygenase is inhibited, support a protective role of HO-1 in sepsis-induced TMA and AKI [32 ▪ ].…”

Section: Heme Oxygenase-1 and Sepsis-associated Thrombotic Microangiomentioning

confidence: 99%

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Heme oxygenase-1 and acute kidney injury

Nath

2014

Current Opinion in Nephrology and Hypertension

110

128

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Purpose of review Heme oxygenase activity, possessed by an inducible heme oxygenase-1 (HO-1) and a constitutive isoform (HO-2), catalyzes the conversion of heme to biliverdin, liberates iron, and generates carbon monoxide. First shown in acute kidney injury (AKI), HO-1 is now recognized as a protectant against diverse insults in assorted tissues. This review summarizes recent contributions to the field of HO-1 and AKI. Recent findings Recent findings elucidate the following: the transcriptional regulation and significance of human HO-1 in AKI; the protective effects of HO-1 in age-dependent and sepsis-related AKI, cardiorenal syndromes, and acute vascular rejection in renal xenografts; the role of heme oxygenase in tubuloglomerular feedback and renal resistance to injury; the basis for cytoprotection by HO-1; the protective properties of ferritin and carbon monoxide; HO-1 and the AKI–chronic kidney disease transition; HO-1 as a biomarker in AKI; the role of HO-1 in mediating the protective effects of specific cytokines, stem cells, and therapeutic agents in AKI; and HO-2 as a protectant in AKI. Summary Recent contributions support, and elucidate the basis for, the induction of HO-1 as a protectant against AKI. Translating such therapeutic potential into a therapeutic reality requires well tolerated and effective modalities for upregulating HO-1 and/or administering its products, which, optimally, should be salutary even when AKI is already established.

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“…Increased levels of plasma sTM can therefore serve as a marker of endothelial injury, and have been found to be associated with worse outcomes in patients with acute coronary syndrome [13]. Furthermore, increased plasma levels of sTM have been reported to be associated with kidney injury induced by sepsis [14] and diabetes [15]. …”

Section: Introductionmentioning

confidence: 99%

Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction

et al. 2014

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IntroductionAcute kidney injury (AKI) following acute myocardial infarction (AMI) is associated with unfavorable prognosis. Endothelial activation and injury were found to play a critical role in the development of both AKI and AMI. This pilot study aimed to determine whether the plasma markers of endothelial injury and activation could serve as independent predictors for AKI in patients with AMI.MethodsThis prospective study was conducted from March 2010 to July 2012 and enrolled consecutive 132 patients with AMI receiving percutaneous coronary intervention (PCI). Plasma levels of thrombomodulin (TM), von Willebrand factor (vWF), angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) were measured on day 1 of AMI. AKI was defined as elevation of serum creatinine of more than 0.3 mg/dL within 48 hours.ResultsIn total, 13 out of 132 (9.8%) patients with AMI developed AKI within 48 hours. Compared with patients without AKI, patients with AKI had increased plasma levels of Ang-2 (6338.28 ± 5862.77 versus 2412.03 ± 1256.58 pg/mL, P = 0.033) and sTM (7.6 ± 2.26 versus 5.34 ± 2.0 ng/mL, P < 0.001), and lower estimated glomerular filtration rate (eGFR) (46.5 ± 20.2 versus 92.5 ± 25.5 mL/min/1.73 m2, P < 0.001). Furthermore, the areas under the receiver operating curves demonstrated that plasma thrombomodulin (TM) and Ang-2 levels on day 1 of AMI had modest discriminative powers for predicting AKI development following AMI (0.796, P <0.001; 0.833, P <0.001; respectively).ConclusionsEndothelial activation, quantified by plasma levels of TM and Ang-2 may play an important role in development of AKI in patients with AMI.

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Heme Oxygenase 1 Modulates Thrombomodulin and Endothelial Protein C Receptor Levels to Attenuate Septic Kidney Injury

Cited by 26 publications

References 29 publications

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

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

Heme oxygenase-1 and acute kidney injury

Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction

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