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Guo S, Zhang D, Dong Y, Shu Y, Wu X, Ni Y, Zhao R, Ma W. Sulfiredoxin-1 accelerates erastin-induced ferroptosis in HT-22 hippocampal neurons by driving heme Oxygenase-1 activation. Free Radic Biol Med 2024; 223:430-442. [PMID: 39159887 DOI: 10.1016/j.freeradbiomed.2024.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 08/21/2024]
Abstract
Ferroptosis, a recently identified non-apoptotic form of cell death, is strongly associated with neurological diseases and has emerged as a potential therapeutic target. Nevertheless, the fundamental mechanisms are still predominantly unidentified. In the current investigation, sulfiredoxin-1 (SRXN1) has been identified as a crucial regulator that enhances the susceptibility to ferroptosis in HT-22 mouse hippocampal cells treated with erastin. Utilizing TMT-based proteomics, a significant increase in SRXN1 expression was observed in erastin-exposed HT-22 cells. Efficient amelioration of erastin-induced ferroptosis was achieved via the knockdown of SRXN1, which resulted in the reduction of intracellular Fe2+ levels and reactive oxygen species (ROS) in HT-22 cells. Notably, the activation of Heme Oxygenase-1 (HO-1) was found to be crucial for inducing SRXN1 expression in HT-22 cells upon treatment with erastin. SRXN1 increased intracellular ROS and Fe2+ levels by activating HO-1 expression, which promoted erastin-induced ferroptosis in HT-22 cells. Inhibiting SRXN1 or HO-1 alleviated erastin-induced autophagy in HT-22 cells. Additionally, upregulation of SRXN1 or HO-1 increased the susceptibility of HT-22 cells to ferroptosis, a process that was counteracted by the autophagy inhibitor 3-Methyladenine (3-MA). These results indicate that SRXN1 is a key regulator of ferroptosis, activating the HO-1 protein through cellular redox regulation, ferrous iron accumulation, and autophagy in HT-22 cells. These findings elucidate a novel molecular mechanism of erastin-induced ferroptosis sensitivity and suggest that SRXN1-HO-1-autophagy-dependent ferroptosis serves as a promising treatment approach for neurodegenerative diseases.
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Affiliation(s)
- Shihui Guo
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Dongxu Zhang
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Yingying Dong
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Yujia Shu
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Xuanfu Wu
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Yingdong Ni
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Ruqian Zhao
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China
| | - Wenqiang Ma
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China; MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China.
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Accommodation in allogeneic and xenogeneic organ transplantation: Prevalence, impact, and implications for monitoring and for therapeutics. Hum Immunol 2023; 84:5-17. [PMID: 36244871 DOI: 10.1016/j.humimm.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/01/2022] [Indexed: 11/04/2022]
Abstract
Accommodation refers to acquired resistance of organs or tissues to immune or inflammatory reactions that might otherwise cause severe injury or rejection. As first observed in ABO-incompatible kidney transplants and heterotopic cardiac xenografts, accommodation was identified when organ transplants continued to function despite the presence of anti-graft antibodies and/or other reactants in the blood of recipients. Recent evidence suggests many and perhaps most organ transplants have accommodation, as most recipients mount B cell responses specific for the graft. Wide interest in the impact of graft-specific antibodies on the outcomes of transplants prompts questions about which mechanisms confer protection against such antibodies, how accommodation might be detected and whether and how rejection could be superimposed on accommodation. Xenotransplantation offers a unique opportunity to address these questions because immune responses to xenografts are easily detected and the pathogenic impact of immune responses is so severe. Xenotransplantation also provides a compelling need to apply these and other insights to decrease the intensity and toxicity of immunosuppression that otherwise could limit clinical application.
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Possemiers H, Pollenus E, Prenen F, Knoops S, Koshy P, Van den Steen PE. Experimental malaria-associated acute kidney injury is independent of parasite sequestration and resolves upon antimalarial treatment. Front Cell Infect Microbiol 2022; 12:915792. [PMID: 36004329 PMCID: PMC9394429 DOI: 10.3389/fcimb.2022.915792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022] Open
Abstract
Malaria remains a important global disease with more than 200 million cases and 600 000 deaths each year. Malaria-associated acute kidney injury (MAKI) may occur in up to 40% of patients with severe malaria and is associated with increased mortality. Histopathological characteristics of AKI in malaria are acute tubular injury, interstitial nephritis, focal segmental glomerulosclerosis, collapsing glomerulopathy and glomerulonephritis. We observed that C57BL/6 mice infected with Plasmodium berghei NK65 (PbNK65) develop MAKI in parallel with malaria-associated acute respiratory distress syndrome (MA-ARDS). MAKI pathology was associated with proteinuria, acute tubular injury and collapse of glomerular capillary tufts, which resolved rapidly after treatment with antimalarial drugs. Importantly, parasite sequestration was not detected in the kidneys in this model. Furthermore, with the use of skeleton binding protein-1 (SBP-1) KO PbNK65 parasites, we found that parasite sequestration in other organs and its subsequent high parasite load are not required for the development of experimental MAKI. Similar proteinuria, histopathological features, and increases in kidney expression of interferon-γ, TNF-α, kidney injury molecule-1 (KIM-1) and heme oxygenase-1 (HO-1) was observed in both infected groups despite a significant difference in parasite load. Taken together, we introduce a model of experimental AKI in malaria with important similarities to AKI in malaria patients. Therefore, this mouse model might be important to further study the pathogenesis of AKI in malaria.
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Affiliation(s)
- Hendrik Possemiers
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, KU, Leuven, Belgium
| | - Emilie Pollenus
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, KU, Leuven, Belgium
| | - Fran Prenen
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, KU, Leuven, Belgium
| | - Sofie Knoops
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, KU, Leuven, Belgium
| | - Priyanka Koshy
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Philippe E. Van den Steen
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, KU, Leuven, Belgium
- *Correspondence: Philippe E. Van den Steen,
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Liu N, Wang H, Han G, Cheng J, Hu W, Zhang J. Enhanced proliferation and differentiation of HO-1 gene-modified bone marrow-derived mesenchymal stem cells in the acute injured kidney. Int J Mol Med 2018; 42:946-956. [PMID: 29749549 PMCID: PMC6034926 DOI: 10.3892/ijmm.2018.3670] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 02/20/2018] [Indexed: 12/12/2022] Open
Abstract
The aim of the present study was to investigate the effect of heme oxygenase-1 (HO-1) overexpression on the survival and differentiation ability of bone marrow‑derived mesenchymal stem cells (BMSCs) in the acute kidney injury (AKI) microenvironment. HO-1-BMSCs and enhanced green fluorescent protein (eGFP)-BMSCs were constructed. Rat ischemia/reperfusion (I/R)‑AKI-kidney homogenate supernatant was prep-ared to treat the BMSCs, eGFP-BMSCs and HO-1-BMSCs in vitro. In the AKI microenvironment, the HO-1-BMSCs exhibited a smaller proportion of cells at the G0/G1 phase, and a larger proportion of cells expressing proliferating cell nuclear antigen (PCNA) and cytokeratin 18 (CK18). Phosphorylated protein kinase B (Akt) and extracellular signal‑regulated kinase (ERK) protein levels were observed to be increased in the HO-1-BMSCs compared with the BMSCs. LY294002 and PD98059 each inhibited the above effects. BMSCs, eGFP-BMSCs and HO-1-BMSCs were implanted into an I/R-AKI rat model. The proportions of PCNA+ BMSCs and CK18+ BMSCs were higher in the HO-1-BMSCs group compared with the BMSCs group, which resulted in a decreased acute tubular necrosis score and improved renal function for the AKI rats. In conclusion, the enhanced proliferation and differentiation of HO-1-BMSCs suggest the beneficial effects of such cells in the BMSC-based therapy of AKI. The mechanism underlying these effects may involve the stimulation of Akt and ERK signaling.
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Affiliation(s)
- Nanmei Liu
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Huiling Wang
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Guofeng Han
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Jin Cheng
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Weifeng Hu
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
| | - Jinyuan Zhang
- Department of Nephrology, The 455th Hospital of PLA, Shanghai 200052, P.R. China
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de Mattos Barbosa MG, Cascalho M, Platt JL. Accommodation in ABO-incompatible organ transplants. Xenotransplantation 2018; 25:e12418. [PMID: 29913044 PMCID: PMC6047762 DOI: 10.1111/xen.12418] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 03/09/2018] [Accepted: 05/03/2018] [Indexed: 12/21/2022]
Abstract
Accommodation refers to a condition in which a transplant (or any tissue) appears to resist immune-mediated injury and loss of function. Accommodation was discovered and has been explored most thoroughly in ABO-incompatible kidney transplantation. In this setting, kidney transplants bearing blood group A or B antigens often are found to function normally in recipients who lack and hence produce antibodies directed against the corresponding antigens. Whether accommodation is owed to changes in anti-blood group antibodies, changes in antigen or a change in the response of the transplant to antibody binding are critically reviewed and a new working model that allows for the kinetics of development of accommodation is put forth. Regardless of how accommodation develops, observations on the fate of ABO-incompatible transplants offer lessons applicable more broadly in transplantation and in other fields.
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Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress. Cell Signal 2017; 34:133-140. [DOI: 10.1016/j.cellsig.2017.03.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/11/2017] [Accepted: 03/19/2017] [Indexed: 12/31/2022]
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Li Z, Xu Y, Liu X, Nie Y, Zhao Z. Urinary heme oxygenase-1 as a potential biomarker for early diabetic nephropathy. Nephrology (Carlton) 2017; 22:58-64. [PMID: 26733347 DOI: 10.1111/nep.12719] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/24/2015] [Accepted: 12/31/2015] [Indexed: 11/28/2022]
Abstract
BACKGROUND Our previous study showed that increases of urinary heme oxygenase-1 (uHO-1) could be a potential biomarker indicating evaluating intrarenal oxidative damage in obstructive nephropathy. Activation of oxidative stress is an important mediator of diabetic nephropathy (DN). The aim of this study was to investigate the clinical implications of uHO-1 levels in patients with type 2 diabetes. METHODS Eighty-four type 2 diabetic patients with normoalbuminuria (n=28), microalbuminuria (n=28), and macroalbuminuria (n=28) were included in this study. Control samples were collected from healthy volunteers (n=28) who had normal albuminuria and renal function. Urine HO-1 levels were evaluated by enzyme-linked immunosorbent assay. RESULTS Urinary HO-1/creatinine (cr.) levels were significantly elevated in diabetic patients with microalbuminuria and macroalbuminuria compared to those in diabetic patients with normoalbuminuria (P<0.001) and control subjects (all P<0.001). In diabetic patients with normoalbuminuria, uHO-1/cr. levels were also higher than those in controls (P<0.001). Multivariate regression analyses revealed that uHO-1/cr. levels were positively correlated to urinary albumin/creatinine ratio and inversely correlated to glomerular filtration rate. Receiver operating characteristic (ROC) curve analysis of uHO-1/cr. levels for early diagnosis and detection of DN revealed that the cut-off value of uHO-1/cr. was 4.59 ng/mg (sensitivity 75%, specificity 78.6%). CONCLUSIONS The findings of this study indicate that increases of urine HO-1 levels can be detected in patients with type 2 diabetes before the onset of significant albuminuria, and associated with renal derangement in patients with established diabetic nephropathy. Urinary HO-1 may be used as an early biomarker for diabetic renal injury.
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Affiliation(s)
- Zhenzhen Li
- Institute of Clinical Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuliang Xu
- Department of Nephrology, the People's Hospital of Hebi, Hebi, China
| | - Xianghua Liu
- Center for Experimental Pathology, Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yali Nie
- Department of Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Zhanzheng Zhao
- Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Bolisetty S, Zarjou A, Agarwal A. Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury. Am J Kidney Dis 2017; 69:531-545. [PMID: 28139396 DOI: 10.1053/j.ajkd.2016.10.037] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 10/22/2016] [Indexed: 01/06/2023]
Abstract
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, the generation of effective therapies against AKI is 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 mediated in part by the by-products of the HO reaction (iron, carbon monoxide, and bile pigments). This review highlights 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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Affiliation(s)
- Subhashini Bolisetty
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL
| | - Abolfazl Zarjou
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL
| | - Anupam Agarwal
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL; Birmingham Veterans Administration Medical Center, Birmingham, AL.
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Askenazi DJ, Halloran B, Patil N, Keeling S, Saeidi B, Koralkar R, Ambalavanan N. Genetic polymorphisms of heme-oxygenase 1 (HO-1) may impact on acute kidney injury, bronchopulmonary dysplasia, and mortality in premature infants. Pediatr Res 2015; 77:793-8. [PMID: 25751573 PMCID: PMC4439308 DOI: 10.1038/pr.2015.44] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 11/19/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Heme oxygenase 1 (HO1) catalyzes heme degradation, and offers protection for several organs, including the kidney. Genetic polymorphisms of HO-1 are associated with poor clinical outcomes in several populations. METHODS POPULATION We prospectively enrolled 117 premature infants (birth weight ≤1,200 g or postgestational age ≤31 wk) and evaluated two DNA genetic variants proximal to the promoter region of HO-1 (GT(n) repeats, and -413T>A SNP). We evaluated how these polymorphisms affect two clinical outcomes: (i) Acute Kidney Injury (AKI)-rise in serum creatinine (SCr) ≥ 0.3 mg/dl or ≥ 150-200% from lowest previous value, (ii) the composite of mortality and bronchopulmonary dysplasia (BPD) defined as receipt of oxygen at 36 wk postmenstrual age. RESULTS AKI occurred in 34/117 (29%) of neonates; 12/117 (10%) died; 29/105 (28%) survivors had BPD. Neonates with TT genotype at 413T>A before the HO-1 promoter had higher rates of AKI (P < 0.05). There was no difference in number of GT(n) repeats and clinical outcomes. CONCLUSION We did not find an association between the GT(n) tandem repeat of HO-1 and AKI nor BPD/mortality. However, infants with TT genotype of the 413T>A genetic alteration had lower incidence of AKI. Further studies using larger cohorts are needed to better understand these relationships.
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Affiliation(s)
- David J Askenazi
- Divisions of Pediatric Nephrology and Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Brian Halloran
- Divisions of Pediatric Nephrology and Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Neha Patil
- Divisions of Pediatric Nephrology and Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Susan Keeling
- Divisions of Pediatric Nephrology and Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Behtash Saeidi
- Divisions of Pediatric Nephrology and Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Rajesh Koralkar
- Divisions of Pediatric Nephrology and Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Namasivayam Ambalavanan
- Divisions of Pediatric Nephrology and Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States
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Heme oxygenase-1 enhances autophagy in podocytes as a protective mechanism against high glucose-induced apoptosis. Exp Cell Res 2015; 337:146-59. [PMID: 25882498 DOI: 10.1016/j.yexcr.2015.04.005] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 04/02/2015] [Accepted: 04/04/2015] [Indexed: 11/21/2022]
Abstract
Injury and loss of podocytes play vital roles in diabetic nephropathy progression. Emerging evidence suggests autophagy, which is induced by multiple stressors including hyperglycemia, plays a protective role. Meanwhile, heme oxygenase-1 (HO-1) possesses powerful anti-apoptotic properties. Therefore, we investigated the impact of autophagy on podocyte apoptosis under diabetic conditions and its association with HO-1. Mouse podocytes were cultured in vitro; apoptosis was detected by flow cytometry. Transmission electron microscopy and biochemical autophagic flux assays were used to measure the autophagy markers microtubule-associated protein 1 light chain 3-II (LC3-II) and beclin-1. LC3-II and beclin-1 expression peaked 12-24h after exposing podocytes to high glucose. Inhibition of autophagy with 3-methyladenine or Beclin-1 siRNAs or Atg 5 siRNAs sensitized cells to apoptosis, suggesting autophagy is a survival mechanism. HO-1 inactivation inhibited autophagy, which aggravated podocyte injury in vitro. Hemin-induced autophagy also protected podocytes from hyperglycemia in vitro and was abrogated by HO-1 siRNA. Adenosine monophosphate-activated protein kinase phosphorylation was higher in hemin-treated and lower in HO-1 siRNA-treated podocytes. Suppression of AMPK activity reversed HO-1-mediated Beclin-1 upregulation and autophagy, indicating HO-1-mediated autophagy is AMPK dependent. These findings suggest HO-1 induction and regulation of autophagy are potential therapeutic targets for diabetic nephropathy.
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Kim H, Moon SY, Kim JS, Baek CH, Kim M, Min JY, Lee SK. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am J Physiol Renal Physiol 2015; 308:F226-36. [DOI: 10.1152/ajprenal.00495.2014] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si)RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1β riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-β, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.
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Affiliation(s)
- Hyosang Kim
- Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea
| | - Soo Young Moon
- Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea
| | - Joon-Seok Kim
- Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea
| | - Chung Hee Baek
- Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea
| | - Miyeon Kim
- Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea
| | - Ji Yeon Min
- Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea
| | - Sang Koo Lee
- Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea
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Gene expression profile in delay graft function: inflammatory markers are associated with recipient and donor risk factors. Mediators Inflamm 2014; 2014:167361. [PMID: 24959002 PMCID: PMC4052172 DOI: 10.1155/2014/167361] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 12/19/2013] [Accepted: 01/15/2014] [Indexed: 12/17/2022] Open
Abstract
Background. Delayed graft function (DGF) remains an important problem after kidney transplantation and reduced long-term graft survival of the transplanted organ. The aim of the present study was to determine if the development of DGF was associated with a specific pattern of inflammatory gene expression in expanded criteria of deceased donor kidney transplantation. Also, we explored the presence of correlations between DGF risk factors and the profile that was found. Methods. Seven days after kidney transplant, a cDNA microarray was performed on biopsies of graft from patients with and without DGF. Data was confirmed by real-time PCR. Correlations were performed between inflammatory gene expression and clinical risk factors. Results. From a total of 84 genes analyzed, 58 genes were upregulated while only 1 gene was downregulated in patients with DGF compared with no DGF (P = 0.01). The most relevant genes fold changes observed was IFNA1, IL-10, IL-1F7, IL-1R1, HMOX-1, and TGF-β. The results were confirmed for IFNA1, IL-1R1, HMOX-1 and TGF-β. A correlation was observed between TGF-β, donor age, and preablation creatinine, but not body mass index (BMI). Also, TGF-β showed an association with recipient age, while IFNA1 correlated with recipient BMI. Furthermore, TGF-β, IFNA1 and HMOX-1 correlated with several posttransplant kidney function markers, such as diuresis, ultrasound Doppler, and glycemia. Conclusions. Overall, the present study shows that DGF is associated with inflammatory markers, which are correlated with donor and recipient DGF risk factors.
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Chen YH, Kuo KL, Hung SC, Hsu CC, Chen YH, Tarng DC. Length polymorphism in heme oxygenase-1 and risk of CKD among patients with coronary artery disease. J Am Soc Nephrol 2014; 25:2669-77. [PMID: 24762402 DOI: 10.1681/asn.2013111205] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The length polymorphism of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with cardiovascular events and mortality in high-risk populations. Experimental data suggest that heme oxygenase-1 protects against kidney disease. However, the association between this polymorphism and long-term risk of CKD in high-risk patients is unknown. We analyzed the allelic frequencies of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter in 386 patients with coronary artery disease recruited from January 1999 to July 2001 and followed until August 31, 2012. The S allele represents short repeats (<27), and the L allele represents long repeats (≥27). The primary renal end points consisted of sustained serum creatinine doubling and/or ESRD requiring long-term RRT. The secondary end points were major adverse cardiovascular events and mortality. At the end of study, the adjusted hazard ratios (95% confidence intervals) for each L allele in the additive model were 1.99 (1.27 to 3.14; P=0.003) for the renal end points, 1.70 (1.27 to 2.27; P<0.001) for major adverse cardiovascular events, and 1.36 (1.04 to 1.79; P=0.03) for mortality. With cardiac events as time-dependent covariates, the adjusted hazard ratio for each L allele in the additive model was 1.91 (1.20 to 3.06; P=0.01) for the renal end points. In conclusion, a greater number of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with higher risk for CKD, cardiovascular events, and mortality among patients with coronary artery disease.
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Affiliation(s)
- Yu-Hsin Chen
- Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, Taipei City Hospital, Yang-Ming Branch, Taipei, Taiwan
| | - Ko-Lin Kuo
- Division of Nephrology, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
| | - Szu-Chun Hung
- Division of Nephrology, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Taipei, Taiwan
| | - Chih-Cheng Hsu
- Division of Geriatrics and Gerontology, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; and
| | | | - Der-Cherng Tarng
- Faculty of Medicine, Institute of Clinical Medicine, and Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Nephrology, Department of Medicine and Immunology Center, Taipei Veterans General Hospital, Taipei, Taiwan
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14
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Respiratory viral infection in neonatal piglets causes marked microglia activation in the hippocampus and deficits in spatial learning. J Neurosci 2014; 34:2120-9. [PMID: 24501353 DOI: 10.1523/jneurosci.2180-13.2014] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Environmental insults during sensitive periods can affect hippocampal development and function, but little is known about peripheral infection, especially in humans and other animals whose brain is gyrencephalic and experiences major perinatal growth. Using a piglet model, the present study showed that inoculation on postnatal day 7 with the porcine reproductive and respiratory syndrome virus (PRRSV) caused microglial activation within the hippocampus with 82% and 43% of isolated microglia being MHC II(+) 13 and 20 d after inoculation, respectively. In control piglets, <5% of microglia isolated from the hippocampus were MHC II(+). PRRSV piglets were febrile (p < 0.0001), anorectic (p < 0.0001), and weighed less at the end of the study (p = 0.002) compared with control piglets. Increased inflammatory gene expression (e.g., IL-1β, IL-6, TNF-α, and IFN-γ) was seen across multiple brain regions, including the hippocampus, whereas reductions in CD200, NGF, and MBP were evident. In a test of spatial learning, PRRSV piglets took longer to acquire the task, had a longer latency to choice, and had a higher total distance moved. Overall, these data demonstrate that viral respiratory infection is associated with a marked increase in activated microglia in the hippocampus, neuroinflammation, and impaired performance in a spatial cognitive task. As respiratory infections are common in human neonates and infants, approaches to regulate microglial cell activity are likely to be important.
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15
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16
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Origassa CST, Câmara NOS. Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury. World J Hepatol 2013; 5:541-9. [PMID: 24179613 PMCID: PMC3812456 DOI: 10.4254/wjh.v5.i10.541] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Revised: 11/08/2012] [Accepted: 11/25/2012] [Indexed: 02/06/2023] Open
Abstract
The activation of heme oxygenase-1 (HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection. In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload (with signs of a chronic hepatitis) and iron deficiency anemia (with paradoxical increased levels of ferritin). Hypoxia induces HO-1 expression in multiple rodent, bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types (endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.
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Affiliation(s)
- Clarice Silvia Taemi Origassa
- Clarice Silvia Taemi Origassa, Laboratory of Experimental and Clinical Immunology, Nephrology Division, Medicine Department, Federal University of São Paulo, 04039-032 São Paulo, Brazil
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17
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Lee JH, Kim JH, Kim JS, Chang JW, Kim SB, Park JS, Lee SK. AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition. Am J Physiol Renal Physiol 2013; 304:F686-97. [PMID: 23324179 DOI: 10.1152/ajprenal.00148.2012] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a novel mechanism that promotes renal fibrosis. Transforming growth factor-β (TGF-β), angiotensin II, aldosterone, high glucose, and urinary albumin are well-known causes of EMT and renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed EMT induced by the above agents in tubular epithelial cells. All experiments were performed using HK-2 cells. Protein expression was measured by Western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry. Exposure of tubular cells to TGF-β (10 ng/ml), angiotensin II (1 μM), aldosterone (100 nM), high glucose (30 mM), and albumin (5 mg/ml) for 5 days induced EMT, as shown by upregulation of α-smooth muscle actin and downregulation of E-cadherin. ROS and NADPH oxidase 4 (Nox4) expression were increased, and antioxidants such as tiron and N-acetylcysteine inhibited EMT induction. Metformin (the best known clinical activator of AMPK) suppressed EMT induction through inhibition of ROS via induction of heme oxygenase-1 and endogenous antioxidant thioredoxin. An AMPK inhibitor (compound C) and AMPK small interfering RNA blocked the effect of metformin, and another AMPK activator [5-aminoimidazole-4-carboxamide-1β riboside (AICAR)] exerted the same effects as metformin. In conclusion, AMPK activation might be beneficial in attenuating the tubulointerstitial fibrosis induced by TGF-β, angiotensin II, aldosterone, high glucose, and urinary albumin.
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Affiliation(s)
- Jang Han Lee
- Department of Internal Medicine, Asan Institute for Life Sciences, College of Medicine, University of Ulsan, Seoul, Korea
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18
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Kitagishi Y, Kobayashi M, Kikuta K, Matsuda S. Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses. DEPRESSION RESEARCH AND TREATMENT 2012; 2012:752563. [PMID: 23320155 PMCID: PMC3535741 DOI: 10.1155/2012/752563] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Revised: 11/09/2012] [Accepted: 11/21/2012] [Indexed: 12/26/2022]
Abstract
Several pharmacological agents acting on monoamine neurotransmission are used for the management of mental illnesses. Regulation of PI3K/AKT and GSK3 pathways may constitute an important signaling center in the subcellular integration of the synaptic neurotransmission. The pathways also modulate neuronal cell proliferation, migration, and plasticity. There are evidences to suggest that inflammation of neuron contributes to the pathology of depression. Inflammatory activation of neuron contributes to the loss of glial elements, which are consistent with pathological findings characterizing the depression. A mechanism of anti-inflammatory reactions from antidepressant medications has been found to be associated with an enhancement of heme oxygenase-1 expression. This induction in brain is also important in neuroprotection and neuroplasticity. As enzymes involved in cell survival and neuroplasticity are relevant to neurotrophic factor dysregulation, the PI3K/AKT/GSK3 may provide an important signaling for the neuroprotection in depression. In this paper, we summarize advances on the involvement of the PI3K/AKT/GSK3 pathways in cell signaling of neuronal cells in mental illnesses.
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Affiliation(s)
- Yasuko Kitagishi
- Department of Environmental Health Science, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
| | - Mayumi Kobayashi
- Department of Environmental Health Science, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
| | - Kanae Kikuta
- Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Satoru Matsuda
- Department of Environmental Health Science, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
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Jiang J, Westberg JA, Andersson LC. Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein. Biochem Biophys Res Commun 2012; 421:274-9. [PMID: 22503972 DOI: 10.1016/j.bbrc.2012.03.151] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 03/30/2012] [Indexed: 11/25/2022]
Abstract
Stanniocalcin 2 (STC2) is a homolog of stanniocalcin 1, a 56kD glycoprotein hormone that originally was found to confer calcitonin-like activity in fish. Human STC2 is expressed in various tissues such as kidney, spleen, heart, and pancreas. STC2 has been demonstrated to be induced by different kinds of stress and display cytoprotective activity, but the molecular mechanism is poorly understood. Heme oxygenase 1 (HO1) degrades heme to biliverdin, carbon monoxide and free iron, and is a stress-responsive protein. Using yeast two-hybrid screening we identified HO1 as a binding partner of STC2. The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence. The binding site for HO1 was located to amino acids 181-200 of STC2. We also found that STC2 binds hemin via a consensus heme regulatory motif. Moreover, STC2 expression was induced by heat shock in HEK293 cells. Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme.
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Affiliation(s)
- Ji Jiang
- Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, PO Box 21, Haartmaninkatu 3, FI-00014 Helsinki, Finland.
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Correa-Costa M, Amano MT, Câmara NOS. Cytoprotection behind heme oxygenase-1 in renal diseases. World J Nephrol 2012; 1:4-11. [PMID: 24175236 PMCID: PMC3782207 DOI: 10.5527/wjn.v1.i1.4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Revised: 10/27/2011] [Accepted: 12/27/2011] [Indexed: 02/06/2023] Open
Abstract
Renal insults are considered a public health problem and are linked to increased rates of morbidity and mortality worldwide. The heme oxygenase (HO) system consists of evolutionary specialized machinery that degrades free heme and produces carbon monoxide, biliverdin and free iron. In this sense, the inducible isoform HO-1 seems to develop an important role and is widely studied. The reaction involved with the HO-1 molecule provides protection to injured tissue, directly by reducing the toxic heme molecule and indirectly by the release of its byproducts. The up regulation of HO-1 enzyme has largely been described as providing antioxidant, antiapoptotic, anti-inflammatory and immunomodulatory properties. Several works have explored the importance of HO-1 in renal diseases and they have provided consistent evidence that its overexpression has beneficial effects in such injuries. So, in this review we will focus on the role of HO-1 in kidney insults, exploring the protective effects of its up regulation and the enhanced deleterious effects of its inhibition or gene deletion.
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Affiliation(s)
- Matheus Correa-Costa
- Matheus Correa-Costa, Mariane Tami Amano, Niels Olsen Saraiva Câmara, Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, 05508-000, São Paulo, Brazil
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21
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Moreno JA, Martín-Cleary C, Gutiérrez E, Toldos O, Blanco-Colio LM, Praga M, Ortiz A, Egido J. AKI Associated with Macroscopic Glomerular Hematuria: Clinical and Pathophysiologic Consequences. Clin J Am Soc Nephrol 2011; 7:175-84. [DOI: 10.2215/cjn.01970211] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Li SD, Wang L, Wang KY, Liang P, Wu G, Zhang KQ, Li QS, Jin FS. Heme oxygenase-1 expression and its significance for acute rejection following kidney transplantation in rats. Transplant Proc 2011; 43:1980-4. [PMID: 21693311 DOI: 10.1016/j.transproceed.2011.03.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Revised: 02/16/2011] [Accepted: 03/09/2011] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To analyze rejection and antiapoptotic effects of heme oxygenase-1 (HO-1) in kidney transplantations, to investigate the protective effects of endogenous HO-1 induced by hemin on acute rat kidney allograft rejection. METHODS We selected 27 Brown-Norway rats and 27 male Lewis rats as donors and recipients, respectively, randomly dividing them into three groups: kidney transplantation alone, hemin treatment group, and cyclosporine (CsA) group (n = 18). Six recipient rats were harvested on the first, fifth, or seventh days after operation among each group to examine histopathologic changes in renal tissue, HO-1 protein expression, and acute rejection as well as to measure serum creatinine values. RESULTS HO-1 expression in both the kidney transplantation model group and the hemin-induced groups were higher compared with the CsA group (P < .05-.01). The expression increased with the aggravation of rejection; the expression in the CsA group also increased after transplantation but was obviously lower than that of the hemin-induced group (P < .01). The rejection process was relatively mild as indenset by histopathologic examination. The serum creatinine levels among the hemin-induced group were lower compared to the kidney transplantation control group (P < .05), but higher compared to the CsA group (P < .05). CONCLUSION HO-1 provided protection of allografts against rejection in rats, but such effects were poorer than those achieved using potent immunosuppressive agents like CsA.
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Affiliation(s)
- S-D Li
- Department of Urology, General Hospital of Chengdu Military Command, Chengdu China.
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23
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Caumartin Y, Stephen J, Deng JP, Lian D, Lan Z, Liu W, Garcia B, Jevnikar AM, Wang H, Cepinskas G, Luke PP. Carbon monoxide-releasing molecules protect against ischemia–reperfusion injury during kidney transplantation. Kidney Int 2011; 79:1080-9. [DOI: 10.1038/ki.2010.542] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Yokoyama T, Shimizu M, Ohta K, Yuno T, Okajima M, Wada T, Toma T, Koizumi S, Yachie A. Urinary heme oxygenase-1 as a sensitive indicator of tubulointerstitial inflammatory damage in various renal diseases. Am J Nephrol 2011; 33:414-20. [PMID: 21502755 DOI: 10.1159/000327020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2010] [Accepted: 03/03/2011] [Indexed: 01/27/2023]
Abstract
BACKGROUND/AIMS In oxidative stress, heme oxygenase-1 (HO-1) plays a pivotal role in maintaining renal function and protecting renal structure, especially in renal tubular epithelial cells. We examined urinary HO-1 (uHO-1) levels to assess whether uHO-1 acts as a sensitive biomarker for detecting tubulointerstitial inflammatory damage in renal diseases. METHODS Immunohistochemical analyses and enzyme-linked immunosorbent assays for uHO-1 were performed using 61 urine samples (supernatants and sediment lysates) from healthy children and renal disease patients. RESULTS Proximal and distal epithelial cells showed higher uHO-1 levels than squamous and urothelial cells. Inflammatory renal disease patients had higher uHO-1 levels than noninflammatory renal disease patients and controls. In IgA nephropathy, patients with interstitial cellular infiltration showed higher uHO-1 levels than those without it. Among patients with increased urinary β(2)-microglobulin or N-acetyl-β-D-glucosaminidase levels, uHO-1 levels increased only in those with renal disease and tubulointerstitial inflammatory damage. uHO-1 levels positively correlated with urinary interleukin-6 in inflammatory renal disease patients. CONCLUSIONS These results indicate that uHO-1 is a potentially useful, novel, and noninvasive biomarker for evaluating the degree of tubulointerstitial inflammatory damage in renal disease.
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Affiliation(s)
- Tadafumi Yokoyama
- Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
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Maternal protein restriction affects gene expression profiles in the kidney at weaning with implications for the regulation of renal function and lifespan. Clin Sci (Lond) 2010; 119:373-84. [DOI: 10.1042/cs20100230] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nutritionally induced alterations in early growth can influence health and disease in later adult life. We have demonstrated previously that low birthweight resulting from maternal protein restriction during pregnancy followed by accelerated growth in rodents was associated with shortened lifespan, whereas protein restriction and slow growth during lactation increased lifespan. Thus early life events can also have a long lasting impact on longevity. In the present study, we show that long-lived PLP (postnatal low protein) mice were protected from developing albuminuria, whereas short-lived recuperated mice demonstrated an age-dependent increase in albuminuria in old age. Microarray analysis of kidneys from 21-day-old mice revealed that gene expression profiles were differentially affected depending on whether protein restriction was imposed during pregnancy or lactation. The differentially expressed genes were involved in diverse biological functions such as cytoprotective functions, vitamin D synthesis, protein homoeostasis, regulation of antioxidant enzymes and cellular senescence. Significantly, up-regulation of Hmox1 (haem oxygenase 1) in kidneys from PLP mice suggests that tissues of long-lived mice are equipped with a better cytoprotective function. In contrast, up-regulation of Nuak2 (NUAK family, SNF1-like kinase 2) and down-regulation of Lonp2 (Lon peptidase 2), Foxo3a (forkhead box O3a), Sod1 (copper/zinc superoxide dismutase) and Sesn1 (sestrin 1) in the kidneys of recuperated offspring suggest that protein homoeostasis and resistance to oxidative stress are compromised, leading to accelerated cellular senescence in these shorter-lived mice.
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26
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Effect of angiotensin II on iron-transporting protein expression and subsequent intracellular labile iron concentration in human glomerular endothelial cells. Hypertens Res 2010; 33:713-21. [PMID: 20431588 DOI: 10.1038/hr.2010.63] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Angiotensin II (Ang II)-induced endothelial injury, which is associated with atherosclerosis, is believed to be mediated by intracellular reactive oxygen species (ROS) through stimulation of nicotinamide adenine dinucleotide phosphate oxidase (NOX). Iron is essential for the amplification of oxidative stress. In this study, we investigated whether Ang II altered iron metabolism and whether the Ang II-induced endothelial injury is attributable to changes in iron metabolism of human glomerular endothelial cells (HGECs). When 90% iron-saturated human transferrin (90% Tf) was applied to HGECs without Ang II, the labile ferrous iron level was same as the effect of control in spite of a significant increase in the total cellular iron concentration. Treatment with Ang II and 30% Tf or 90% Tf significantly (P<0.01) increased the intracellular iron concentration, as well as labile ferrous iron and protein oxidation levels, compared with the effect of separate administration of each compound. Ang II treatment facilitated the protein expression of the Tf receptor, divalent metal transporter 1, and ferroportin 1 in a dose- and time-dependent manner. It was also found that simultaneous exposure of HGECs to Ang II and 90% Tf accelerated hydroxyl radical production, as shown by using an electron paramagnetic resonance spectrometer. These results suggest that Ang II not only induces production of ROS by NOX activation but also iron incorporation followed by an increase in labile iron in HGECs. Both of these events may participate in the progression of oxidative stress because of endothelial cell dysfunction through ferrous iron-mediated ROS generation.
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Yan J, Yang S, Zhang J, Zhai C, Zhu T. BMP6 attenuates oxidant injury in HK-2 cells via Smad-dependent HO-1 induction. Free Radic Biol Med 2009; 46:1275-82. [PMID: 19245827 DOI: 10.1016/j.freeradbiomed.2009.02.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2008] [Revised: 01/24/2009] [Accepted: 02/02/2009] [Indexed: 12/01/2022]
Abstract
Oxidative stress is involved in a variety of kidney diseases, and heme oxygenase 1 (HO-1) induction is a protective response to oxidative stress. Downregulation of bone morphogenetic protein 6 (BMP6) is associated with renal damage in intrauterine growth-restricted newborns. However, it is unknown whether BMP6 has a renoprotective effect or HO-1 induction property. In this study, we demonstrate that BMP6 effectively protects renal proximal tubule cells (HK-2) against hydrogen peroxide (H(2)O(2))-induced cell injury. BMP6 also increased HO-1 gene expression and activity of HO. Inhibition of de novo gene expression, the HO inhibitor ZnPPIX, HO-1 knockdown, or the carbon monoxide (CO) scavenger hemoglobin attenuated the cytoprotective effect of BMP6, whereas HO-1 constitutive expression, the HO-1 inducer hemin, or the hemin metabolites bilirubin and CO ameliorated H(2)O(2)-induced cell injury. Stimulation of HK-2 cells with BMP6 activated Smad signaling but not mitogen-activated protein kinases. In addition, BMP6-mediated induction of HO-1 expression and increase in HO activity were inhibited by Smad5 knockdown. Furthermore, deletion or mutation of the Smad-binding element in the HO-1 promoter also inhibited BMP6-induced luciferase activity. In summary, these findings suggest that induction of HO-1 through a Smad-dependent mechanism is responsible for the cytoprotective effect of BMP6 in H(2)O(2)-mediated renal cell injury.
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Affiliation(s)
- Jidong Yan
- Medical College of Nankai University, Tianjin, China
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28
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Chin HJ, Cho HJ, Lee TW, Na KY, Yoon HJ, Chae DW, Kim S, Jeon US, Do JY, Park JW, Yoon KW, Shin YT, Lee KW, Na KR, Cha DR, Kang YS, The Progressive REnal disease and Medical Informatics and gEnomics Research (PREMIER) members. The heme oxygenase-1 genotype is a risk factor to renal impairment of IgA nephropathy at diagnosis, which is a strong predictor of mortality. J Korean Med Sci 2009; 24 Suppl:S30-7. [PMID: 19194559 PMCID: PMC2633190 DOI: 10.3346/jkms.2009.24.s1.s30] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2008] [Accepted: 11/03/2008] [Indexed: 11/20/2022] Open
Abstract
The induction of heme oxygenase-1 (HO-1) ameliorates oxidative stress and inflammatory process, which play important roles in IgA nephropathy. We hypothesized length polymorphism in the promoter region of the HO-1 gene, which is related to the level of gene transcription, is associated with disease severity of IgA nephropathy. The subjects comprised 916 patients with IgA nephropathy and gene data. Renal impairment was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) at diagnosis. The short (S: <23), medium (M: 23-28), and long (L: >28) (GT) repeats in the HO-1 gene was determined. The frequencies of S/S, S/M, M/M, S/L, L/M, and L/L genotypes were 7.2%, 6.9%, 3.1%, 30.8%, 22.7%, and 29.4%, respectively. The baseline characteristics were not different. In the S/S genotypic group, the renal impairment rate was 18.2%, which was lower than 32.2% in the group with M/M, L/M, or L/L genotype. The odds ratio of renal impairment in S/S genotype, compared to that in M/M, L/M, or L/L genotype, was 0.216 (95% confidence interval, 0.060-0.774, p=0.019). The HO-1 gene promoter length polymorphism was related to the renal impairment of IgA nephropathy at diagnosis, which is an important risk factor for mortality in IgA nephropathy patients.
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Affiliation(s)
- Ho Jun Chin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Renal Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Jin Cho
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Tae Woo Lee
- Renal Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ki Young Na
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyung Jin Yoon
- Clinical Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Dong-Wan Chae
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Renal Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Suhnggwon Kim
- Renal Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Un Sil Jeon
- Biotechnology Center, Pohang University of Science and Technology, Pohang, Korea
| | - Jun-Young Do
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Jong-Won Park
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Kyung-Woo Yoon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Young-Tai Shin
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Kang Wook Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Ki-Ryang Na
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Dae Ryong Cha
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea
| | - Young Sun Kang
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea
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Chen JH, Jones RH, Tarry-Adkins J, Smith NH, Ozanne SE. Adverse effects of reduced oxygen tension on the proliferative capacity of rat kidney and insulin-secreting cell lines involve DNA damage and stress responses. Exp Cell Res 2008; 314:3075-80. [PMID: 18692496 PMCID: PMC2631166 DOI: 10.1016/j.yexcr.2008.07.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2008] [Revised: 07/16/2008] [Accepted: 07/19/2008] [Indexed: 10/29/2022]
Abstract
Standard cell culture conditions do not reflect the physiological environment in terms of oxygen tension (20% vs 3%). The effects of lowering oxygen tension on cell proliferation in culture can be beneficial as well as detrimental depending on the cell line studied, but the molecular mechanism underlying such effects is not fully understood. We observed that the proliferative capacity of the rat cell lines NRK and INS-1 was inhibited when cultured under 3% oxygen as compared to 20% oxygen. Suppression of proliferation in NRK cells was accompanied by induction of DNA double strand breaks whereas in INS-1 cells it was accompanied by up-regulation of p53 and p27. Although Sirt1 was up-regulated in both cell lines by 3% oxygen the effects on antioxidant enzymes (MnSOD, CuZnSOD and catalase) were cell line specific. Marked up-regulation of heme oxygenase-1 (HO-1) was detected in both NRK and INS-1 cells when cultured in 3% oxygen. HO-1 expression can be readily induced by exposure to hydrogen peroxide in culture. These results suggest that reduced oxygen tension suppresses the proliferative capacity of these two cell lines through a stress response that is similar to an oxidative stress response but the molecular events that lead to the reduced cell proliferation are cell line specific.
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Affiliation(s)
- Jian-Hua Chen
- Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
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