scholarly journals Kidney injury by cyclosporine A is aggravated in heme oxygenase-1 deficient mice and involves regulation of microRNAs

2018 ◽  
Author(s):  
Agnieszka Łoboda ◽  
Olga Mucha ◽  
Paulina Podkalicka ◽  
Mateusz Sobczak ◽  
Anna Miksza-Cybulska ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Cyclosporine A ◽  
Renal Damage ◽  
Kidney Injury ◽  
Protective Role ◽  
Immunosuppressive Drug ◽  
Heme Oxygenase 1 ◽  
Knock Out ◽  
Deficient Mice

Cyclosporine A (CsA), a widely used immunosuppressive drug, exerts nephrotoxic activities, as demonstrated by increased tubulointerstitial fibrosis, inflammation and podocyte damage. Recently, a number of microRNAs expressed in the kidney have been reported to be elevated during renal damage. Our aim was to investigate the effect of CsA on selected microRNAs in the mouse kidney after CsA treatment. Moreover, as heme oxygenase-1 (HO-1, encoded by the Hmox1 gene) was shown to play a protective role during kidney disorders, we assessed whether HO-1 deficiency in vivo influences the CsA-regulated microRNAs’ expression. We have observed that the pro-fibrotic miR-21 and pro-apoptotic miR-34a expression was upregulated in kidneys of HO-1 deficient mice and it was further enhanced by CsA. Concomitantly, the level of anti-fibrotic microRNAs, belonging to miR-29 and miR-200 families, was down-regulated after CsA treatment. Generally, Hmox1 knock-out (Hmox1–/–) animals were more susceptible to CsA treatment, as the mortality rate was 4 out of 9 Hmox1–/– mice, and increased fibrosis (Tgfb2, Pai1), inflammation (Il6) and apoptosis (Cdkn1a-p21) were noticed in the HO-1 deficient kidneys. In summary, our data demonstrate that CsA induces significant changes in the expression of renal microRNAs and emphasize HO-1 deficiency as an important factor contributing to the CsA-mediated renal toxicity.

scholarly journals Regulation of heme oxygenase-1 gene by peptidoglycan involves the interaction of Elk-1 and C/EBPα to increase expression

2010 ◽  
Vol 298 (6) ◽  
pp. L870-L879 ◽  
Author(s):  
Chi-Chih Hung ◽  
Xiaoli Liu ◽  
Min-Young Kwon ◽  
Young-Ho Kang ◽  
Su Wol Chung ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Promoter Activity ◽  
Inflammatory Responses ◽  
Systemic Infection ◽  
Protective Role ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Gram Positive ◽  
And Function

Heme oxygenase (HO)-1 is a cytoprotective enzyme with anti-inflammatory properties. HO-1 is induced during a systemic inflammatory response, and expression of HO-1 is beneficial during sepsis of a Gram-positive source. Systemic infection from Gram-positive organisms has emerged as an important cause of sepsis, with Staphylococcus aureus as a common etiology. An important mediator of Gram-positive infections is peptidoglycan (PGN), a cell wall component of these organisms. Here, we demonstrate that HO-1 played an important, protective role in vivo, as mice deficient in HO-1 were very sensitive to the lethal effects of PGN derived from S. aureus. PGN induced HO-1 protein and mRNA levels, and this regulation occurred at the level of gene transcription. The PGN-responsive region of the HO-1 promoter (from −117 to −66 bp) contains a functional EBS, and Ets proteins are known to be involved in the regulation of inflammatory responses. We showed previously that Ets factors (activators Ets-2 and Ets-1 and repressor Elk-3) regulate HO-1 expression by Gram-negative endotoxin. However, during exposure to a Gram-positive stimulus in the present study, Elk-1 was a potent activator of HO-1 in conjunction with PGN. The ability of Elk-1 to induce HO-1 promoter activity was independent of direct DNA binding, but rather occurred by interacting with the CCAAT/enhancer-binding protein-α (C/EBPα), which binds to DNA. Moreover, silencing of C/EBPα in macrophages prevented induction of HO-1 promoter activity by either Elk-1 or PGN. These data provide further insight into the regulation and function of HO-1 by a mediator of Gram-positive bacteria.

scholarly journals Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury

2011 ◽  
Vol 301 (1) ◽  
pp. F162-F170 ◽  
Author(s):  
Qingqing Wei ◽  
William D. Hill ◽  
Yunchao Su ◽  
Shuang Huang ◽  
Zheng Dong
Keyword(s):  
Acute Kidney Injury ◽  
Heme Oxygenase ◽  
Cell Injury ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells

Granulocyte colony-stimulating factor (G-CSF) is renoprotective during acute kidney injury (AKI) induced by ischemia and cisplatin nephrotoxicity; however, the underlying mechanism is not entirely clear. Rhabdomyolysis is another important clinical cause of AKI, due to the release of nephrotoxins (e.g., heme) from disrupted muscles. The current study has determined the effects of G-CSF on rhabdomyolysis-associated AKI using in vivo and in vitro models. In C57BL/6 mice, intramuscular injection of glycerol induced AKI, which was partially prevented by G-CSF pretreatment. Consistently, glycerol-induced renal tissue damage was ameliorated by G-CSF. In addition, animal survival following the glycerol injection was improved from ∼30 to ∼70% by G-CSF. In cultured renal tubular cells, hemin-induced apoptosis was also suppressed by G-CSF. Interestingly, G-CSF induced heme oxygenase-1 (HO-1, a critical enzyme for heme/hemin degradation and detoxification) in both cultured tubular cells and mouse kidneys. Blockade of HO-1 with protoporphyrin IX zinc(II) (ZnPP) could largely diminish the protective effects of G-CSF. Together, these results demonstrated the renoprotective effects of G-CSF in rhabdomyolysis-associated AKI. Notably, G-CSF may directly protect against tubular cell injury under the disease condition by inducing HO-1.

scholarly journals 323: Pravastatin improves pregnancy outcome and placental development in heme oxygenase-1 deficient mice

2018 ◽  
Vol 218 (1) ◽  
pp. S202-S203
Author(s):  
Abraham Tsur ◽  
Flora Kalish ◽  
Jordan Burgess ◽  
Hui Zhao ◽  
Kerriann Casey ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Placental Development ◽  
Deficient Mice

scholarly journals Hyperbaric Oxygen Preconditioning Upregulates Heme OxyGenase-1 and Anti-Apoptotic Bcl-2 Protein Expression in Spontaneously Hypertensive Rats with Induced Postischemic Acute Kidney Injury

2021 ◽  
Vol 22 (3) ◽  
pp. 1382
Author(s):  
Jelena Nesovic Ostojic ◽  
Milan Ivanov ◽  
Nevena Mihailovic-Stanojevic ◽  
Danijela Karanovic ◽  
Sanjin Kovacevic ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protein Expression ◽  
Hyperbaric Oxygen ◽  
Heme Oxygenase ◽  
Spontaneously Hypertensive Rats ◽  
Wistar Rats ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

Renal ischemia and reperfusion (I/R) injury is the most common cause of acute kidney injury (AKI). Pathogenesis of postischemic AKI involves hemodynamic changes, oxidative stress, inflammation process, calcium ion overloading, apoptosis and necrosis. Up to date, therapeutic approaches to treat AKI are extremely limited. Thus, the aim of this study was to evaluate the effects of hyperbaric oxygen (HBO) preconditioning on citoprotective enzyme, heme oxygenase-1 (HO-1), pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins expression, in postischemic AKI induced in normotensive Wistar and spontaneously hypertensive rats (SHR). The animals were randomly divided into six experimental groups: SHAM-operated Wistar rats (W-SHAM), Wistar rats with induced postischemic AKI (W-AKI) and Wistar group with HBO preconditioning before AKI induction (W-AKI + HBO). On the other hand, SHR rats were also divided into same three groups: SHR-SHAM, SHR-AKI and SHR-AKI + HBO. We demonstrated that HBO preconditioning upregulated HO-1 and anti-apoptotic Bcl-2 protein expression, in both Wistar and SH rats. In addition, HBO preconditioning improved glomerular filtration rate, supporting by significant increase in creatinine, urea and phosphate clearances in both rat strains. Considering our results, we can also say that even in hypertensive conditions, we can expect protective effects of HBO preconditioning in experimental model of AKI.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

scholarly journals Pharmacological Targeting of Heme Oxygenase-1 in Osteoarthritis

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 419
Author(s):  
Yohei Sanada ◽  
Sho Joseph Ozaki Tan ◽  
Nobuo Adachi ◽  
Shigeru Miyaki
Keyword(s):  
Heme Oxygenase ◽  
Redox Homeostasis ◽  
Synovial Fibroblasts ◽  
Protective Role ◽  
Joint Disease ◽  
Heme Oxygenase 1 ◽  
Transcriptional Level ◽  
Related Factor ◽  
Mobility Limitations ◽  
Therapeutic Implications

Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. Here, we review the protective role of HO-1 in OA with a focus on the regulatory mechanisms that mediate HO-1 activity.

FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 3997-4002 ◽  
Author(s):  
Dirk Meyer ◽  
Carsten Schiller ◽  
Jürgen Westermann ◽  
Shozo Izui ◽  
Wouter L. W. Hazenbos ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Knock Out ◽  
Effector Cells ◽  
Igg Isotypes ◽  
Knock Out Mice ◽  
Deficient Mice ◽  
Experimental Autoimmune

Abstract In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcγRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.

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