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Chienwichai K, Phirom S, Wuttiputhanun T, Leelahavanichkul A, Townamchai N, Avihingsanon Y, Udomkarnjananun S. A systematic review and meta-analysis of factors contributing to post-kidney transplant anemia and the effect of erythropoietin-stimulating agents. Syst Rev 2024; 13:278. [PMID: 39533400 PMCID: PMC11556001 DOI: 10.1186/s13643-024-02709-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The effects of various risk and associated factors on post-kidney transplant anemia (PTA) have not been fully compared and estimated. This meta-analysis aims to elucidate factors contributing to PTA and determine the influence of erythropoietin-stimulating agents (ESAs) on renal outcomes, thus offering potential pathways for enhanced management strategies post-transplant. METHODS A systematic review was conducted in electronical database. Studies reporting on risk factors (with cause-effect relationships) and associated factors (without definite cause-effect relationships) of PTA, and the effects of ESAs on post-kidney transplant outcomes, were included. Pooled odds ratios (ORs) and weighted mean differences (WMDs) were analyzed using random-effects models. RESULTS This systematic review encompassed 38,233 patients from 85 studies. Factors increased PTA risk included African American, older donor age, human antigen leukocyte mismatches, and low pre-transplant hemoglobin levels. Poor allograft function, high interleukine-6, Cytomegalovirus, delayed graft function, allograft rejections, immunosuppressive medications, and renin-angiotensin system blockades were associated with PTA. Native autosomal dominant polycystic kidney disease was a protective factor against PTA. Administration of ESAs with the aim of normalizing hemoglobin levels in patients with chronic allograft dysfunction slowed the decline in eGFR and reduce the risk of death, with a pooled OR of 0.36 (95% CI: 0.14 to 0.89; p = 0.040). CONCLUSIONS The risks and associated factors for PTA have been elucidated, underscoring the need for individualized treatment approaches. Late ESA therapy, aimed at hemoglobin normalization, suggests a renal-protective effect and reduced mortality, which should be considered in the management of PTA. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42024545330.
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Affiliation(s)
| | - Supitchaya Phirom
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
| | - Thunyatorn Wuttiputhanun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
- Excellence Center for Organ Transplantation (ECOT), King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
| | - Asada Leelahavanichkul
- Department of Microbiology, Immunology Unit, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Center of Excellence On Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natavudh Townamchai
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
- Excellence Center for Organ Transplantation (ECOT), King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
- Center of Excellence in Renal Immunology and Renal Transplantation, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yingyos Avihingsanon
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
- Excellence Center for Organ Transplantation (ECOT), King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
- Center of Excellence in Renal Immunology and Renal Transplantation, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand.
- Excellence Center for Organ Transplantation (ECOT), King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand.
- Department of Microbiology, Immunology Unit, Chulalongkorn University, Bangkok, Thailand.
- Department of Microbiology, Center of Excellence On Translational Research in Inflammation and Immunology (CETRII), Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
- Center of Excellence in Renal Immunology and Renal Transplantation, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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Wu G, Cao B, Zhai H, Liu B, Huang Y, Chen X, Ling H, Ling S, Jin S, Yang X, Wang J. EPO promotes the progression of rheumatoid arthritis by inducing desialylation via increasing the expression of neuraminidase 3. Ann Rheum Dis 2024; 83:564-575. [PMID: 38272667 PMCID: PMC11041559 DOI: 10.1136/ard-2023-224852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 01/17/2024] [Indexed: 01/27/2024]
Abstract
OBJECTIVE Erythropoietin (EPO) known as an erythrocyte-stimulating factor is increased in patients with rheumatoid arthritis (RA). Nevertheless, the function of EPO in the process of RA and relative mechanism needs to be further clarified. METHODS The level of EPO in serum and synovial fluid from patients with RA and healthy controls was determined by . Collagen-induced arthritis (CIA) mice were constructed to confirm the role of EPO on RA pathogenesis. Differentially expressed genes (DEGs) of EPO-treated fibroblast-like synoviocyte (FLS) were screened by transcriptome sequencing. The transcription factor of neuraminidase 3 (NEU3) of DEGs was verified by double luciferase reporting experiment, DNA pulldown, electrophoretic mobility shift assay and chromatin immunoprecipitation-quantitative PCR (qPCR) assay. RESULTS The overexpression of EPO was confirmed in patients with RA, which was positively associated with Disease Activity Score 28-joint count. Additionally, EPO intervention could significantly aggravate the joint destruction in CIA models. The upregulation of NEU3 was screened and verified by transcriptome sequencing and qPCR in EPO-treated FLS, and signal transducer and activator of transcription 5 was screened and verified to be the specific transcription factor of NEU3. EPO upregulates NEU3 expression via activating the Janus kinase 2 (JAK2)-STAT5 signalling pathway through its receptor EPOR, thereby to promote the desialylation through enhancing the migration and invasion ability of FLS, which is verified by JAK2 inhibitor and NEU3 inhibitor. CONCLUSION EPO, as a proinflammatory factor, accelerates the process of RA through transcriptional upregulation of the expression of NEU3 by JAK2/STAT5 pathway.
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Affiliation(s)
- Gan Wu
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ben Cao
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Haige Zhai
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bin Liu
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuan Huang
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaowei Chen
- Department of Immunology and Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hanzhi Ling
- Department of Immunology and Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Sunwang Ling
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shengwei Jin
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xinyu Yang
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianguang Wang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Autoimmune Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Kittur FS, Hung CY, Li PA, Sane DC, Xie J. Asialo-rhuEPO as a Potential Neuroprotectant for Ischemic Stroke Treatment. Pharmaceuticals (Basel) 2023; 16:610. [PMID: 37111367 PMCID: PMC10143832 DOI: 10.3390/ph16040610] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/11/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently translated in clinical trials. The clinical failure of rhuEPOM was thought to be mainly due to its erythropoietic activity-associated side effects. To exploit its tissue-protective property, various EPO derivatives with tissue-protective function only have been developed. Among them, asialo-rhuEPO, lacking terminal sialic acid residues, was shown to be neuroprotective but non-erythropoietic. Asialo-rhuEPO can be prepared by enzymatic removal of sialic acid residues from rhuEPOM (asialo-rhuEPOE) or by expressing human EPO gene in glycoengineered transgenic plants (asialo-rhuEPOP). Both types of asialo-rhuEPO, like rhuEPOM, displayed excellent neuroprotective effects by regulating multiple cellular pathways in cerebral I/R animal models. In this review, we describe the structure and properties of EPO and asialo-rhuEPO, summarize the progress on neuroprotective studies of asialo-rhuEPO and rhuEPOM, discuss potential reasons for the clinical failure of rhuEPOM with acute ischemic stroke patients, and advocate future studies needed to develop asialo-rhuEPO as a multimodal neuroprotectant for ischemic stroke treatment.
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Affiliation(s)
- Farooqahmed S. Kittur
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
| | - Chiu-Yueh Hung
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
| | - P. Andy Li
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
| | - David C. Sane
- Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA;
| | - Jiahua Xie
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; (C.-Y.H.); (P.A.L.)
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Wang J, Matsushita K, Zhong J, Ma LJ, Yang HC, Fogo AB. Low-Dose Erythropoietin Amplifies Beneficial Effects of Angiotensin II Blockade on Glomerulosclerosis. J Transl Med 2023; 103:100015. [PMID: 37039147 PMCID: PMC11610902 DOI: 10.1016/j.labinv.2022.100015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 09/02/2022] [Accepted: 09/20/2022] [Indexed: 01/11/2023] Open
Abstract
Exogenous erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). Concerns about the possible adverse effect of EPO on the progression of CKD have been raised owing to nonerythroid cell effects. We investigated the effects of low-dose EPO, independent of correcting anemia, on existing glomerulosclerosis. Adult mice underwent 5/6 nephrectomy and were randomized into the following 4 groups at week 8 after surgery: vehicle (VEH), losartan (angiotensin II type 1 receptor blocker [ARB]), darbepoetin-α (DA), or combination (DA+ARB). Four weeks later, mice were euthanized, followed by evaluation of renal structure and function. Glomerular endothelial cells and podocytes were cultured to evaluate the effects of DA on cell migration, apoptosis, and Akt signaling. ARB reduced blood pressure, albuminuria, and the level of serum creatinine and increased hematocrit compared with VEH, whereas low-dose DA only reduced the level of serum creatinine. Combination treatment showed a trend to increase hematocrit and survival compared with ARB alone. Combination treatment but not ARB alone significantly reduced the progression of glomerulosclerosis compared with VEH. Low-dose DA resulted in more preserved glomerular and peritubular capillary endothelial cells with increased p-Akt and even further endothelial cell preservation in combination with ARB. In cultured glomerular endothelial cells, angiotensin II induced more apoptosis, reduced migration, and decreased p-Flk1, a receptor for the proangiogenic vascular endothelial growth factor. DA counteracted these injuries and increased p-Akt, a key factor in angiogenesis and cell survival. DA also protected cultured podocytes against transforming growth factor β-induced apoptosis and synaptopodin loss. Low-dose EPO directly protects glomerular and peritubular endothelial cells via Akt phosphorylation. Therefore, treatment using a combination of low-dose EPO and ARB results in less progression of glomerulosclerosis in an experimental CKD model.
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Affiliation(s)
- Jiayi Wang
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Keizo Matsushita
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jianyong Zhong
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Li-Jun Ma
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hai-Chun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Shin HJ, Ko E, Jun I, Kim HJ, Lim CH. Effects of perioperative erythropoietin administration on acute kidney injury and red blood cell transfusion in patients undergoing cardiac surgery: A systematic review and meta-analysis. Medicine (Baltimore) 2022; 101:e28920. [PMID: 35244046 PMCID: PMC8896477 DOI: 10.1097/md.0000000000028920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 02/07/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The renoprotective effects of erythropoietin (EPO) are well-known; however, the optimal timing of EPO administration remains controversial. Red blood cell (RBC) transfusion is an independent risk factor for cardiac surgery-associated acute kidney injury (CSA-AKI). We aimed to evaluate the efficacy of EPO on CSA-AKI and RBC transfusion according to the timing of administration. METHODS We searched the Cochrane Library, EMBASE, and MEDLINE databases for randomized controlled trials. The primary outcome was the incidence of CSA-AKI following perioperative EPO administration, and the secondary outcomes were changes in serum creatinine, S-cystatin C, S-neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, length of hospital and intensive care unit (ICU) stay, volume of RBC transfusion, and mortality. The subgroup analysis was stratified according to the timing of EPO administration in relation to surgery. RESULTS Eight randomized controlled trials with 610 patients were included in the study. EPO administration significantly decreased the incidence of CSA-AKI (odds ratio: 0.60, 95% confidence interval [CI]: 0.43-0.85, P = .004; I2 = 52%; P for heterogeneity = .04), intra-operative RBC transfusion (standardized mean difference: -0.30, 95% CI: -0.55 to -0.05, P = .02; I2 = 15%, P for heterogeneity = .31), and hospital length of stay (mean difference: -1.54 days, 95% CI: -2.70 to -0.39, P = .009; I2 = 75%, P for heterogeneity = .001) compared with control groups. Subgroup analyses revealed that pre-operative EPO treatment significantly reduced the incidence of CSA-AKI, intra-operative RBC transfusion, serum creatinine, and length of hospital and ICU stay. CONCLUSION Pre-operative administration of EPO may reduce the incidence of CSA-AKI and RBC transfusion, but not in patients administered EPO during the intra-operative or postoperative period. Therefore, pre-operative EPO treatment can be considered to improve postoperative outcomes by decreasing the length of hospital and ICU stay in patients undergoing cardiac surgery.
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Affiliation(s)
- Hyeon Ju Shin
- Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Eunji Ko
- Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Injae Jun
- Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hyun Jung Kim
- Department of Preventive Medicine, Institute for Evidence-based Medicine Cochrane Korea, Republic of Korea
| | - Choon Hak Lim
- Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
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Hafizi R, Imeri F, Wenger RH, Huwiler A. S1P Stimulates Erythropoietin Production in Mouse Renal Interstitial Fibroblasts by S1P 1 and S1P 3 Receptor Activation and HIF-2α Stabilization. Int J Mol Sci 2021; 22:ijms22179467. [PMID: 34502385 PMCID: PMC8430949 DOI: 10.3390/ijms22179467] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/27/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Erythropoietin (Epo) is the critical hormone for erythropoiesis. In adults, Epo is mainly produced by a subset of interstitial fibroblasts in the kidney, with minor amounts being produced in the liver and the brain. In this study, we used the immortalized renal interstitial fibroblast cell line FAIK F3-5 to investigate the ability of the bioactive sphingolipid sphingosine 1-phosphate (S1P) to stimulate Epo production and to reveal the mechanism involved. Stimulation of cells with exogenous S1P under normoxic conditions (21% O2) led to a dose-dependent increase in Epo mRNA and protein levels and subsequent release of Epo into the medium. S1P also enhanced the stabilization of HIF-2α, a key transcription factor for Epo expression. S1P-stimulated Epo mRNA and protein expression was abolished by HIF-2α mRNA knockdown or by the HIF-2 inhibitor compound 2. Furthermore, the approved S1P receptor modulator FTY720, and its active form FTY720-phosphate, both exerted a similar effect on Epo expression as S1P. The effect of S1P on Epo was antagonized by the selective S1P1 and S1P3 antagonists NIBR-0213 and TY-52156, but not by the S1P2 antagonist JTE-013. Moreover, inhibitors of the classical MAPK/ERK, the p38-MAPK, and inhibitors of protein kinase (PK) C and D all blocked the effect of S1P on Epo expression. Finally, the S1P and FTY720 effects were recapitulated in the Epo-producing human neuroblastoma cell line Kelly, suggesting that S1P receptor-dependent Epo synthesis is of general relevance and not species-specific. In summary, these data suggest that, in renal interstitial fibroblasts, which are the primary source of plasma Epo, S1P1 and 3 receptor activation upregulates Epo under normoxic conditions. This may have a therapeutic impact on disease situations such as chronic kidney disease, where Epo production is impaired, causing anemia, but it may also have therapeutic value as Epo can mediate additional tissue-protective effects in various organs.
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Affiliation(s)
- Redona Hafizi
- Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland; (R.H.); (F.I.)
| | - Faik Imeri
- Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland; (R.H.); (F.I.)
| | - Roland H. Wenger
- Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland;
| | - Andrea Huwiler
- Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland; (R.H.); (F.I.)
- Correspondence: ; Tel.: +41-316-323-214
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Ghanbari E, Solouk A, Mehdinavaz Aghdam R, Haghbin Nazarpak M, Ahmadi Tafti SH. A novel substrate based on electrospun polyurethane nanofibers and electrosprayed polyvinyl alcohol microparticles for recombinant human erythropoietin delivery. J Biomed Mater Res A 2021; 110:181-195. [PMID: 34309172 DOI: 10.1002/jbm.a.37275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/29/2021] [Accepted: 07/07/2021] [Indexed: 11/08/2022]
Abstract
After myocardial infarction caused by a heart attack, endothelial cells need to be preserved in order to regenerate new capillaries. Moreover, sufficient mechanical support is necessary for the infarcted myocardium to pump the blood. Herein, we designed a novel substrate containing polyurethane (PU) nanofibrous layers and recombinant human erythropoietin (rhEPO)-loaded microparticles for both controlled releases of rhEPO and mechanical support of myocardium. In this system, the single-layer (SL) and double-layer (DL) PU nanofibers were electrospun, and then microparticles with different rhEPO:polyvinyl alcohol (PVA) ratios were electrosprayed on the layers. The in vitro release behavior of rhEPO from SL substrates was not satisfactory, and then the study focused on DL patches in which the release profile was in accordance with Korsmeyer-Peppas model. The release exponent of 0.89 for the DL PU/120PVA:1rhEPO represented zero-order release. The results inferred that these substrates possessed highly tailored mechanical properties; Young's modulus and ultimate tensile strength of the substrates were 74-172 kPa and 7.4-9.9 MPa, respectively. The rhEPO release from the substrates was leading to the proper adhesion of endothelial cells and more than 95% cell viability. The results indicated that the patch of elastic nanofibers and microparticles offered a potential substrate for simultaneous rhEPO delivery to endothelial cells and also mechanically supporting the infarcted myocardium.
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Affiliation(s)
- Elmira Ghanbari
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Atefeh Solouk
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | | | - Masoumeh Haghbin Nazarpak
- New Technologies Research Center, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
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Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells. Toxins (Basel) 2021; 13:toxins13030190. [PMID: 33800744 PMCID: PMC7999264 DOI: 10.3390/toxins13030190] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/25/2021] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
Ochratoxin A (OTA) is a mycotoxin occurring in foods consumed by humans. Recently, there has been growing global concern regarding OTA toxicity. The main target organ of OTA is the kidney, but the mechanism underlying renal toxicity is not well known. In this study, human-derived proximal tubular epithelial cells, HK-2 cells, were used for RNA-sequencing (RNA-seq) and transcriptome analysis. In total, 3193 differentially expressed genes were identified upon treatment with 200 nM OTA in HK-2 cells; of these, 2224 were upregulated and 969 were downregulated. Transcriptome analysis revealed that OTA significantly affects hypoxia, epithelial-mesenchymal transition (EMT), apoptosis, and xenobiotic metabolism pathways in kidney cells. Quantitative real-time PCR analysis showed gene expression patterns similar to RNA-seq analysis. Expression of EMT markers (E-cadherin and fibronectin), apoptosis markers (caspase-3 and Bax), and kidney injury molecule-1 (KIM-1) was suppressed by inhibiting AhR expression using siRNA, and the related transcription factors, Smad2/3, and HIF-1α were downregulated. Smad2/3 suppression with siRNA could inhibit fibronetcin, caspase-3, Bax, and KIM-1 expression. Fibronetcin, caspase-3, Bax, and KIM-1 expression could be increased with HIF-1α suppression with siRNA. Taken together, these findings suggest that OTA-mediated kidney toxicity via the AhR-Smad2/3-HIF-1α signaling pathways leads to induction of EMT, apoptosis, and kidney injury.
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Liu H, Su LL, Ren Y, Wang WY. Rehmannia glutinosa polysaccharide increases the expression of erythropoietin and vascular endothelial growth factor in rats with chronic renal failure by activating hypoxia-inducible factor-2α. Pharmacogn Mag 2021. [DOI: 10.4103/pm.pm_13_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Kawasaki R, Tashiro Y, Yogo K, Serizawa K, Aizawa K, Endo K, Hirata M. Prolonged Duration of Erythropoiesis-Stimulating Agents' Action Delays Disease Progression in Anti-Thy 1 Antibody-Induced Chronic Glomerulonephritis Rats. Pharmacology 2020; 106:45-52. [PMID: 32829322 DOI: 10.1159/000506995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 03/04/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Although erythropoiesis-stimulating agents (ESAs) exert renoprotective effects in renal disease models, it has not been revealed whether the prolonged duration of action of ESAs contributes to their renoprotective effects. OBJECTIVE We examined whether the prolonged duration of ESAs' action contributes to their renoprotective effects by comparing a divided administration of a short-acting ESA, epoetin beta (EPO), or a single administration of a long-acting ESA, epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), to a single administration of EPO in chronic glomerulonephritis (GN) rats. MATERIALS AND METHODS Chronic GN was induced by intravenous injection of anti-Thy 1.1 antibody (0.6 mg/kg) into uninephrectomized rats (day 0). Chronic GN rats were intravenously injected once with vehicle (disease control; DC), EPO 5,000 IU/kg (single EPO), or C.E.R.A. 25 μg/kg (single C.E.R.A.) on day 1; or 3 times during the first week with EPO 1,667 IU/kg from day 1 (divided EPO; total 5,000 IU/kg). Hemoglobin (Hb) level and urinary total protein (U-TP) level which are the indexes of hematopoiesis and renoprotective effects, respectively, were measured several times over 8 weeks. RESULTS Divided EPO and single C.E.R.A. increased Hb levels more greatly than did single EPO. In all chronic GN rats, elevated U-TP levels decreased transiently 2 weeks after chronic GN induction and then flared again. Single EPO significantly suppressed this exacerbation of U-TP levels compared to DC. Divided EPO and single C.E.R.A. each significantly suppressed the exacerbation of U-TP levels compared to single EPO. CONCLUSION Prolonged duration of ESAs' action contributed significantly to their renoprotective effects.
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Affiliation(s)
- Ryohei Kawasaki
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
| | - Yoshihito Tashiro
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
| | - Kenji Yogo
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
| | - Kenichi Serizawa
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
| | - Ken Aizawa
- Oncology Lifecycle Management Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Koichi Endo
- Medical Science Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Michinori Hirata
- Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan,
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11
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Kittur FS, Hung CY, Zhu C, Shajahan A, Azadi P, Thomas MD, Pearce JL, Gruber C, Kallolimath S, Xie J. Glycoengineering tobacco plants to stably express recombinant human erythropoietin with different N-glycan profiles. Int J Biol Macromol 2020; 157:158-169. [PMID: 32348856 PMCID: PMC8349175 DOI: 10.1016/j.ijbiomac.2020.04.199] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/31/2020] [Accepted: 04/23/2020] [Indexed: 12/26/2022]
Abstract
Plant-based expression system has many potential advantages to produce biopharmaceuticals, but plants cannot be directly used to express human glycoproteins because of their differences in glycosylation abilities from mammals. To exploit plant-based expression system for producing recombinant human erythropoietin (rhuEPO), we glycoengineered tobacco plants by stably introducing seven to eight mammalian genes including a target human EPO into tobacco in order to generate capacities for β1,4-galactosylation, bisecting N-acetylglucosamine (GlcNAc) and sialylation. Wild type human β1,4-galactosyltransferase gene (GalT) or a chimeric GalT gene (ST/GalT) was co-expressed to produce rhuEPO bearing β1,4-galactose-extended N-glycan chains as well as compare their β1,4-galactosylation efficiencies. Five mammalian genes encoding enzymes/transporter for sialic acid biosynthesis, transport and transfer were co-expressed to build sialylation capacity in plants. The human MGAT3 was co-expressed to produce N-glycan chains with bisecting GlcNAc. Our results demonstrated that the above transgenes were incorporated into tobacco genome and transcribed. ST/GalT was found to be more efficient than GalT for β1,4-galactosylation. Furthermore, co-expressing MGAT3 generated N-glycans likely bearing bisected GlcNAc. However, our current efforts did not result in generating sialylation capacity. Created transgenic plants expressing EPO and ST/GalT could be used to produce rhuEPO with high proportion of β1,4-galactose-extended N-glycan chains for tissue protective purposes.
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Affiliation(s)
- Farooqahmed S Kittur
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - Chiu-Yueh Hung
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - Chuanshu Zhu
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA; College of Plant Protection, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Asif Shajahan
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
| | - Parastoo Azadi
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
| | - Michelle D Thomas
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - Jackson L Pearce
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - Clemens Gruber
- Department of Chemistry, University of Natural Resources and Applied Life Sciences, Muthgasse 18, 1190 Vienna, Austria
| | - Somanath Kallolimath
- Department of Applied Genetics and Cell Biology, University of Natural Resources and Applied Life Sciences, Muthgasse 18, 1190 Vienna, Austria
| | - Jiahua Xie
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
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12
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Guillemet L, Jamme M, Bougouin W, Geri G, Deye N, Vivien B, Varenne O, Pène F, Mira JP, Barat F, Treluyer JM, Hermine O, Carli P, Coste J, Cariou A. Effects of early high-dose erythropoietin on acute kidney injury following cardiac arrest: exploratory post hoc analyses from an open-label randomized trial. Clin Kidney J 2020; 13:413-420. [PMID: 32699621 PMCID: PMC7367106 DOI: 10.1093/ckj/sfz068] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 04/29/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is frequent in patients resuscitated from cardiac arrest (CA) and may worsen outcome. Experimental data suggest a renoprotective effect by treating these patients with a high dose of erythropoietin (Epo) analogues. We aimed to evaluate the efficacy of epoetin alpha treatment on renal outcome after CA. METHODS We did a post hoc analysis of the Epo-ACR-02 trial, which randomized patients with a persistent coma after a witnessed out-of-hospital CA. Only patients admitted in one intensive care unit were analysed. In the intervention group, patients received five intravenous injections of Epo spaced 12 h apart during the first 48 h, started as soon as possible after resuscitation. In the control group, patients received standard care without Epo. The main endpoint was the proportion of patients with persistent AKI defined by Kidney Disease: Improving Global Outcomes criteria at Day 2. Secondary endpoints included the occurrence of AKI through Day 7, estimated glomerular filtration rate (eGFR) at Day 28, haematological indices and adverse events. RESULTS A total of 162 patients were included in the primary analysis (74 in the Epo group, 88 in the control group). Baseline characteristics were similar in the two groups. At Day 2, 52.8% of the patients (38/72) in the intervention group had an AKI, as compared with 54.4% of the patients (46/83) in the control group (P = 0.74). There was no significant difference between the two groups regarding the proportion of patients with AKI through Day 7. Among patients with persistent AKI at Day 2, 33% (4/12) in the intervention group had an eGFR <75 mL/min/1.73 m2 compared with 25% (3/12) in the control group at Day 28 (P = 0.99). We found no significant differences in haematological indices or adverse events. CONCLUSION After CA, early administration of Epo did not confer any renal protective effect as compared with standard therapy.
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Affiliation(s)
- Lucie Guillemet
- Medical Intensive Care Unit, Cochin Hospital (AP-HP), Paris, France
- Paris Descartes University, Paris, France
| | - Matthieu Jamme
- Medical Intensive Care Unit, Cochin Hospital (AP-HP), Paris, France
| | - Wulfran Bougouin
- Medical Intensive Care Unit, Cochin Hospital (AP-HP), Paris, France
- Paris Descartes University, Paris, France
- INSERM U970 (Team 4), Parisian Cardiovascular Research Center, Paris Descartes University, Paris, France
| | - Guillaume Geri
- Medical Intensive Care Unit, Cochin Hospital (AP-HP), Paris, France
- Paris Descartes University, Paris, France
- INSERM U970 (Team 4), Parisian Cardiovascular Research Center, Paris Descartes University, Paris, France
| | - Nicolas Deye
- Medical Intensive Care Unit, Lariboisière Hospital (AP-HP) and INSERM U942, Paris, France
| | - Benoît Vivien
- Paris Descartes University, Paris, France
- SAMU 75, Necker Hospital (AP-HP), Paris, France
| | - Olivier Varenne
- Paris Descartes University, Paris, France
- Cardiology Department, Cochin University Hospital (AP-HP), Paris, France
| | - Frédéric Pène
- Medical Intensive Care Unit, Cochin Hospital (AP-HP), Paris, France
- Paris Descartes University, Paris, France
| | - Jean-Paul Mira
- Medical Intensive Care Unit, Cochin Hospital (AP-HP), Paris, France
- Paris Descartes University, Paris, France
| | - Florence Barat
- Clinical Trial Unit, Central Pharmacy, AP-HP, Paris, France
| | - Jean-Marc Treluyer
- Paris Descartes University, Paris, France
- Clinical Research Unit, Paris Centre and Paris Descartes University, Paris, France
| | - Olivier Hermine
- Paris Descartes University, Paris, France
- Hematology Department, Necker Hospital (AP-HP)—Imagine institute—INSERM U1123 CNRS erl 8654 - Labex des Globules Rouges Grex, Paris, France
| | - Pierre Carli
- Paris Descartes University, Paris, France
- SAMU 75, Necker Hospital (AP-HP), Paris, France
| | - Joël Coste
- Paris Descartes University, Paris, France
- Biostatistics and Epidemiology Unit, Hôtel-Dieu Hospital (AP-HP), Paris, France
| | - Alain Cariou
- Medical Intensive Care Unit, Cochin Hospital (AP-HP), Paris, France
- Paris Descartes University, Paris, France
- INSERM U970 (Team 4), Parisian Cardiovascular Research Center, Paris Descartes University, Paris, France
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13
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Prevention of Ischemia-Reperfusion Injury in Human Kidney Transplantation: A Meta-Analysis of Randomized Controlled Trials. Nephrourol Mon 2020. [DOI: 10.5812/numonthly.101590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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14
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Zhou J, Bai Y, Jiang Y, Tarun P, Feng Y, Huang R, Fu P. Immunomodulatory role of recombinant human erythropoietin in acute kidney injury induced by crush syndrome via inhibition of the TLR4/NF-κB signaling pathway in macrophages. Immunopharmacol Immunotoxicol 2020; 42:37-47. [PMID: 31971040 DOI: 10.1080/08923973.2019.1706555] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objective: The present study aimed to investigate whether recombinant human erythropoietin (rHuEPO) plays an immunomodulatory function by regulating the TLR4/NF-κB signaling pathway.Materials and methods: C57BL/6 mice were intraperitoneally injected with rHuEPO and, half an hour later, with 50% glycerol at the dose of 7.5 ml/kg to induce crush syndrome (CS)-acute kidney injury (AKI). The levels of TNF-α, IL-1β, IL-6, serum creatinine (Scr), and creatine kinase (CK) were measured. The kidney tissues were analyzed by HE staining, and macrophage infiltration was detected by immunohistochemistry. Double immunofluorescence staining, RT-qPCR, and western blotting were conducted to analyze TLR4/NF-κB p65 expression. Ferrous myoglobin was co-cultured with RAW264.7 cells to mimic crush injury and the production of proinflammatory cytokines. The expression levels of TLR4 and NF-κB p65 were measured.Results: In vivo study results revealed that rHuEPO ameliorated renal function, tissue damage, production of proinflammatory cytokines, and macrophage infiltration in the kidneys. The protein and mRNA expression levels of genes involved in the TLR4/NF-κB signaling pathway in CS-induced AKI mice were upregulated (p < .05). Meanwhile, the expression levels of TLR4, NF-κB p65, and proinflammatory cytokines in RAW264.7 cells were downregulated in CS-AKI mice injected with rHuEPO (p < .05).Conclusions: Our results demonstrated the immunomodulatory capacity of rHuEPO and confirmed that rHuEPO exerts protective effects against CS-induced AKI by regulating the TLR4/NF-κB signaling pathway in macrophages. Therefore, our findings highlight the therapeutic potential of rHuEPO in improving the prognosis of CS-AKI patients.
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Affiliation(s)
- Jiaojiao Zhou
- Division of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yajun Bai
- Department of Nephrology, Nanchong Central Hospital, Nanchong, Sichuan, China
| | - Yong Jiang
- Sichuan Center for Disease Control and Prevention, Chengdu, Sichuan, China
| | - Padamata Tarun
- West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yuying Feng
- Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Rongshuang Huang
- Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ping Fu
- Kidney Research Institute, Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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15
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El-Gendy AA, Elsaed WM, Abdallah HI. Potential role of estradiol in ovariectomy-induced derangement of renal endocrine functions. Ren Fail 2019; 41:507-520. [PMID: 31216906 PMCID: PMC6586115 DOI: 10.1080/0886022x.2019.1625787] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Menopause is an important physiological event associated with structural and functional changes in the kidneys. An animal model of bilateral ovariectomy was used to study the effects of estrogen depletion, replacement and antiestrogen on renal structure and endocrine function. Sixty female rats were divided into six groups; group I was the control group, the remaining five groups underwent ovariectomy: group II received no treatment. The other groups received estradiol in group III, tamoxifen in group IV, estradiol followed by tamoxifen in group V and tamoxifen followed by estradiol in group VI. Serum creatinine, blood urea nitrogen, and endocrine functions of kidney were measured. Tissue samples were examined both microscopically for beta estrogen receptors and ultrastructurally for cell changes. Groups II, IV & VI showed a significant increase in creatinine, blood urea nitrogen, renal malondialdehyde, renal erythropoietin, plasma renin and plasma prostaglandin E2 and a significant decrease in renal antioxidants and serum vitamin D3. Groups III &V had a significant decrease in creatinine, blood urea nitrogen, renal malondialdehyde and renal erythropoietin with an increase in renal antioxidants, plasma prostaglandin E2 and serum vitamin D3. Histopathological and ultrastructural examinations revealed atrophic tubular changes in group II. The changes were less marked in groups III &V and more extensive in groups IV & VI. Estrogen receptor beta staining showed progressively increased expression in the absence of estrogen. Structural and most endocrine functions of the kidney were significantly affected by estradiol deficiency. Estradiol replacement exhibited a protective effect on renal tissue and endocrine functions.
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Affiliation(s)
- Ahmed A El-Gendy
- a Department of Medical Physiology, Faculty of Medicine , Taibah University , Madinah , Saudi Arabia.,b Department of Medical Physiology, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - Wael M Elsaed
- c Department of Anatomy & Embryology, Faculty of Medicine , Taibah University , Madinah , Saudi Arabia.,d Department of Anatomy & Embryology, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - Hesham I Abdallah
- c Department of Anatomy & Embryology, Faculty of Medicine , Taibah University , Madinah , Saudi Arabia.,e Department of Anatomy & Embryology, Faculty of Medicine , Ain Shams University , Cairo , Egypt
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16
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Hassan AED, Shaat EA, Deif MM, El Azhary NM, Omar EM. Effect of erythropoietin hormone supplementation on renal functions and the level of hypoxia-inducible factor-1α in rat kidneys with experimentally induced diabetic nephropathy. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2013.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Affiliation(s)
- Alaa El Din Hassan
- Department of Physiology, Faculty of Medicine, Alexandria University, Egypt
| | - Eman A. Shaat
- Department of Biochemistry, Faculty of Medicine, Alexandria University, Egypt
| | - Maha M. Deif
- Department of Physiology, Faculty of Medicine, Alexandria University, Egypt
| | | | - Eman M. Omar
- Department of Physiology, Faculty of Medicine, Alexandria University, Egypt
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17
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Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair. Cells 2019; 8:cells8030207. [PMID: 30823476 PMCID: PMC6468851 DOI: 10.3390/cells8030207] [Citation(s) in RCA: 177] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 02/21/2019] [Accepted: 02/25/2019] [Indexed: 02/07/2023] Open
Abstract
Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions. Hypoxia-inducible factors (HIFs) are the "master" transcription factors responsible for gene expression in hypoxia. Recent researches demonstrate that HIFs play an important role in kidney injury and repair by regulating HIF target genes, including microRNAs. However, there are controversies regarding the pathological roles of HIFs in kidney injury and repair. In this review, we describe the regulation, expression, and functions of HIFs, and their target genes and related functions. We also discuss the involvement of HIFs in AKI and kidney repair, presenting HIFs as effective therapeutic targets.
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18
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Güven Bağla A, Içkin Gülen M, Ercan F, Aşgün F, Ercan E, Bakar C. Changes in kidney tissue and effects of erythropoietin after acute heart failure. Biotech Histochem 2018; 93:340-353. [PMID: 29671622 DOI: 10.1080/10520295.2018.1443347] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
Abstract
Impairment of cardiac function causes renal damage. Renal failure after heart failure is attributed to hemodynamic derangement including reduced renal perfusion and increased venous pressure. One mechanism involves apoptosis and is defined as cardiorenal syndrome type 1. Erythropoietin (EPO) is a cytokine that induces erythropoiesis under hypoxic conditions. Hypoxia inducible factor 1 alpha (HIF-1α) plays a regulatory role in cellular response to hypoxia. Protective effects of EPO on heart, kidney and nervous system are unrelated to red blood cell production. We investigated early changes in and effects of EPO on renal tissues of rats with myocardial infarction by morphology and immunohistochemistry. Coronary artery ligation was used to induce myocardial infarction in Wistar rats. Group 1 comprised sham operated rats; groups 2, 3 and 4 included rats after coronary artery ligation that were sacrificed 6 h after ligation and that were treated with saline, 5,000 U/kg EPO or 10,000 U/kg EPO, respectively; group 5 included rats sacrificed 1 h after ligation. Group 2 showed increased renal tubule damage. Significantly less tubule damage was observed in EPO treated groups. EPO and EPO receptor (EPO-R) immunostaining intensities increased slightly for group 5 and became more intense for group 2. EPO and EPO-R immunostaining was observed in the interstitial area, glomerular cells and tubule epithelial cells of EPO treated groups. HIF-1α immunostaining was observed in collecting tubules in the medulla only in group 2. Caspase-3 immunostaining is an indicator of apoptosis. Caspase-3 staining intensity decreased in renal medulla of EPO treated groups. EPO treatment may exert a protective effect on the renal tissues of patients with cardiorenal syndrome.
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Affiliation(s)
- A Güven Bağla
- a Çanakkale Onsekiz Mart University , School of Medicine, Department of Histology and Embryology , Çanakkale
| | - M Içkin Gülen
- a Çanakkale Onsekiz Mart University , School of Medicine, Department of Histology and Embryology , Çanakkale
| | - F Ercan
- b Marmara University , School of Medicine, Department of Histology and Embryology , Istanbul
| | - F Aşgün
- c Çanakkale Onsekiz Mart University , School of Medicine, Department of Cardiovascular Surgery , Çanakkale
| | - E Ercan
- d Department of Cardiology , Medical Park Hospital , Izmir
| | - C Bakar
- e Çanakkale Onsekiz Mart University , School of Medicine, Department of Public Health , Çanakkale , Turkey
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19
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Wu SH, Lu IC, Lee SS, Kwan AL, Chai CY, Huang SH. Erythropoietin attenuates motor neuron programmed cell death in a burn animal model. PLoS One 2018; 13:e0190039. [PMID: 29385149 PMCID: PMC5791978 DOI: 10.1371/journal.pone.0190039] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 12/07/2017] [Indexed: 02/07/2023] Open
Abstract
Burn-induced neuromuscular dysfunction may contribute to long-term morbidity; therefore, it is imperative to develop novel treatments. The present study investigated whether erythropoietin (EPO) administration attenuates burn-induced motor neuron apoptosis and neuroinflammatory response. To validate our hypothesis, a third-degree hind paw burn rat model was developed by bringing the paw into contact with a metal surface at 75°C for 10 s. A total of 24 male Sprague–Dawley rats were randomly assigned to four groups: Group A, sham-control; Group B, burn-induced; Group C, burn + single EPO dose (5000 IU/kg i.p. at D0); and Group D, burn + daily EPO dosage (3000 IU/kg/day i.p. at D0–D6). Two treatment regimens were used to evaluate single versus multiple doses treatment effects. Before sacrifice, blood samples were collected for hematological parameter examination. The histological analyses of microglia activation, iNOS, and COX-2 in the spinal cord ventral horn were performed at week 1 post-burn. In addition, we examined autophagy changes by biomarkers of LC3B and ATG5. The expression of BCL-2, BAX, cleaved caspase-3, phospho-AKT, and mTOR was assessed simultaneously through Western blotting. EPO administration after burn injury attenuated neuroinflammation through various mechanisms, including the reduction of microglia activity as well as iNOS and COX-2 expression in the spinal cord ventral horn. In addition, the expression of phospho-AKT, mTOR and apoptotic indicators, such as BAX, BCL-2, and cleaved caspase-3, was modulated. Furthermore, the activity of burn-induced autophagy in the spinal cord ventral horn characterized by the expression of autophagic biomarkers, LC3B and ATG5, was reduced after EPO administration. The present results indicate that EPO inhibits the AKT-mTOR pathway to attenuate burn-induced motor neuron programmed cell death and microglia activation. EPO can modulate neuroinflammation and programmed cell death and may be a therapeutic candidate for neuroprotection.
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Affiliation(s)
- Sheng-Hua Wu
- Department of Anesthesiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Anesthesiology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - I-Cheng Lu
- Department of Anesthesiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Anesthesiology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Su-Shin Lee
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Aij-Lie Kwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chee-Yin Chai
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Hung Huang
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail:
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Tolwani A, Paganini E, Joannidis M, Zamperetti N, Verbine A, Vidyasagar V, Clark W, Ronco C. Treatment of Patients with Cardiac Surgery Associated-Acute Kidney Injury. Int J Artif Organs 2018; 31:190-6. [DOI: 10.1177/039139880803100212] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Members of the Acute Dialysis Quality Initiative (ADQI) participated in a 3-day conference in Vicenza in May 2007 to evaluate the available literature on this topic and draft consensus recommendations for research studies in this area. This report summarizes the available evidence and describes the key questions that will need to be addressed with the goal of standardizing the care of patients with cardiac surgery-associated acute kidney injury (CSA-AKI) and improving outcomes.
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Affiliation(s)
- A. Tolwani
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama - USA
| | - E. Paganini
- Dialysis and Extracorporeal Treatment, Department of Nephrology and Hypertension, Cleveland Clinic Foundation, Cleveland, Ohio - USA
| | - M. Joannidis
- Medical ICU, Department of Internal Medicine, Medical University of Innsbruck, Innsbruck - Austria
| | - N. Zamperetti
- Department of Anesthesia and Intensive Care Medicine, San Bortolo Hospital - International Renal Research Institute Vicenza (IRRIV), Vicenza - Italy
| | - A. Verbine
- Department of Nephrology, Dialysis and Renal Transplant, San Bortolo Hospital - International Renal Research Institute Vicenza (IRRIV), Vicenza - Italy
| | - V. Vidyasagar
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama - USA
| | - W. Clark
- Medical Strategy and Therapy Development, Gambro, Indianapolis, Indiana - USA
- Indiana University School of Medicine, Indianapolis, Indiana - USA
| | - C. Ronco
- Department of Nephrology, Dialysis and Renal Transplant, San Bortolo Hospital - International Renal Research Institute Vicenza (IRRIV), Vicenza - Italy
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Shi M, Flores B, Li P, Gillings N, McMillan KL, Ye J, Huang LJS, Sidhu SS, Zhong YP, Grompe MT, Streeter PR, Moe OW, Hu MC. Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a "U-shaped" relationship. Am J Physiol Renal Physiol 2017; 314:F501-F516. [PMID: 29187371 DOI: 10.1152/ajprenal.00306.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a "U-shaped" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.
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Affiliation(s)
- Mingjun Shi
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Brianna Flores
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Peng Li
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas.,Department of Nephrology, Yu-Huang-Ding Hospital, Qingdao University , Yantai, Shandong , People's Republic of China
| | - Nancy Gillings
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Kathryn L McMillan
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Jianfeng Ye
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Lily Jun-Shen Huang
- Department of Cell Biology, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Sachdev S Sidhu
- Banting and Best Department of Medical Research and Department of Molecular Genetics, The Donnelly Centre, University of Toronto , Toronto, Ontario , Canada
| | - Yong-Ping Zhong
- Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University , Portland, Oregon
| | - Maria T Grompe
- Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University , Portland, Oregon
| | - Philip R Streeter
- Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University , Portland, Oregon
| | - Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas.,Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas.,Department of Physiology, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Ming Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center , Dallas, Texas.,Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
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22
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Bonnas C, Wüstefeld L, Winkler D, Kronstein-Wiedemann R, Dere E, Specht K, Boxberg M, Tonn T, Ehrenreich H, Stadler H, Sillaber I. EV-3, an endogenous human erythropoietin isoform with distinct functional relevance. Sci Rep 2017; 7:3684. [PMID: 28623280 PMCID: PMC5473850 DOI: 10.1038/s41598-017-03167-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 04/25/2017] [Indexed: 01/14/2023] Open
Abstract
Generation of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced EPO transcript characterized by deletion of exon 3 (hEPOΔ3). We show co-regulation of EPO and hEPOΔ3 in human diseased tissue. The expression of hEPOΔ3 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEPOΔ3 and EPO in response to hypoxic conditions was also observed in HepG2 cell cultures. Using LC-ESI-MS/MS, we provide first evidence for the existence of hEPOΔ3 derived protein EV-3 in human serum from healthy donors. Contrary to EPO, recombinant EV-3 did not promote early erythroid progenitors in cultures of human CD34+ haematopoietic stem cells. Repeated intraperitoneal administration of EV-3 in mice did not affect the haematocrit. Similar to EPO, EV-3 acted anti-apoptotic in rat hippocampal neurons exposed to oxygen-glucose deprivation. Employing the touch-screen paradigm of long-term visual discrimination learning, we obtained first in vivo evidence of beneficial effects of EV-3 on cognition. This is the first report on the presence of a naturally occurring EPO protein isoform in human serum sharing non-erythropoietic functions with EPO.
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Affiliation(s)
| | - Liane Wüstefeld
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
| | - Daniela Winkler
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
| | - Romy Kronstein-Wiedemann
- German Red Cross Blood Donor Service North-East, Institute of Transfusion Medicine, Dresden, Germany
| | - Ekrem Dere
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
| | - Katja Specht
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Melanie Boxberg
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Torsten Tonn
- German Red Cross Blood Donor Service North-East, Institute of Transfusion Medicine, Dresden, Germany
- Department of Experimental Transfusion Medicine, Medical Faculty Carl Gustav Carus, Technische Universität Desden, Dresden, Germany
| | - Hannelore Ehrenreich
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
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23
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Wu S, Yang C, Xu N, Wang L, Liu Y, Wang J, Shen X. The Protective Effects of Helix B Surface Peptide on Experimental Acute Liver Injury Induced by Carbon Tetrachloride. Dig Dis Sci 2017; 62:1537-1549. [PMID: 28365917 DOI: 10.1007/s10620-017-4553-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 03/23/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND To investigate the protective effects of helix B surface peptide (HBSP) on acute liver injury induced by carbon tetrachloride (CCl4). METHODS HBSP (8 nmol/kg) was intraperitoneally injected into C57 BL/6 mice 2 h after CCl4 administration. Serum and liver tissue samples were collected 24 h after injury. Liver function and histological injuries were evaluated. Inflammatory cell infiltration and cytokines were examined and hepatocytes apoptosis was measured. The human liver cell line LO2 and murine primary hepatocytes were stimulated by CCl4 with and without HBSP treatment and glutathione peroxidase activity, cell survival, and apoptosis were evaluated. In addition, we examined the PI3K/Akt/mTORC1 pathway to elucidate the mechanism underlying HBSP-mediated protection in acute liver injury. RESULTS HBSP significantly decreased serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and pro-inflammatory cytokines in liver tissues after CCl4 injection compared with those in the control group. Immunohistochemical staining indicated that the number of CD3-, CD8-, and CD68-positive cells and the expression of cleaved caspase-3 were significantly decreased by HBSP treatment. Additionally, HBSP reduced apoptosis in vivo. In an in vitro study, the glutathione peroxidase activity and survival rate increased, while the total apoptotic rate was reduced in the HBSP-treated group compared with that in the control group after CCl4 treatment. HBSP activated the PI3K/Akt/mTORC1 pathway, which was confirmed by the PI3K inhibitor LY294002 both in vivo and in vitro. Furthermore, HBSP increased the survival of mice with acute liver injury, and this effect was abolished by LY294002. CONCLUSIONS HBSP is a potential therapeutic agent against acute liver injury induced by CCl4.
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Affiliation(s)
- Shengdi Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Institute of Liver Diseases, Shanghai, 200032, China
| | - Cheng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Nuo Xu
- Department of Respiration, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lingyan Wang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yun Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jiyao Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Institute of Liver Diseases, Shanghai, 200032, China
| | - Xizhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Department of Internal Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Shanghai Institute of Liver Diseases, Shanghai, 200032, China. .,Key Laboratory of Medical Molecule Virology, Ministry of Education and Health, Shanghai, 200032, China.
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24
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Arthur E, Kittur FS, Lin Y, Hung CY, Sane DC, Xie J. Plant-Produced Asialo-Erythropoietin Restores Pancreatic Beta-Cell Function by Suppressing Mammalian Sterile-20-like Kinase (MST1) and Caspase-3 Activation. Front Pharmacol 2017; 8:208. [PMID: 28469576 PMCID: PMC5395651 DOI: 10.3389/fphar.2017.00208] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 04/03/2017] [Indexed: 01/12/2023] Open
Abstract
Pancreatic beta-cell death adversely contributes to the progression of both type I and II diabetes by undermining beta-cell mass and subsequently diminishing endogenous insulin production. Therapeutics to impede or even reverse the apoptosis and dysfunction of beta-cells are urgently needed. Asialo-rhuEPO, an enzymatically desialylated form of recombinant human erythropoietin (rhuEPO), has been shown to have cardioprotective and neuroprotective functions but with no adverse effects like that of sialylated rhuEPO. Heretofore, the anti-apoptotic effect of asialo-rhuEPO on pancreatic beta-cells has not been reported. In the current study, we investigated the cytoprotective properties of plant-produced asialo-rhuEPO (asialo-rhuEPOP) against staurosporine-induced cell death in the pancreatic beta-cell line RIN-m5F. Our results showed that 60 IU/ml asialo-rhuEPOP provided 41% cytoprotection while 60 IU/ml rhuEPO yielded no effect. Western blotting results showed that asialo-rhuEPOP treatment inhibited both MST1 and caspase-3 activation with the retention of PDX1 and insulin levels close to untreated control cells. Our study provides the first evidence indicating that asialo-rhuEPOP-mediated protection involves the reduction of MST1 activation, which is considered a key mediator of apoptotic signaling in beta-cells. Considering the many advantages its plant-based expression, asialo-rhuEPOP could be potentially developed as a novel and inexpensive agent to treat or prevent diabetes after further performing studies in cell-based and animal models of diabetes.
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Affiliation(s)
- Elena Arthur
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, DurhamNC, USA
| | - Farooqahmed S Kittur
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, DurhamNC, USA
| | - Yuan Lin
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, DurhamNC, USA.,School of Basic Medical Sciences, Ningxia Medical UniversityYinchuan, China
| | - Chiu-Yueh Hung
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, DurhamNC, USA
| | - David C Sane
- Carilion Clinic and Virginia Tech Carilion School of Medicine, RoanokeVA, USA
| | - Jiahua Xie
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, DurhamNC, USA
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25
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Nematbakhsh M, Pezeshki Z, Eshraghi Jazi F, Mazaheri B, Moeini M, Safari T, Azarkish F, Moslemi F, Maleki M, Rezaei A, Saberi S, Dehghani A, Malek M, Mansouri A, Ghasemi M, Zeinali F, Zamani Z, Navidi M, Jilanchi S, Shirdavani S, Ashrafi F. Cisplatin-Induced Nephrotoxicity; Protective Supplements and Gender Differences. Asian Pac J Cancer Prev 2017; 18:295-314. [PMID: 28345324 PMCID: PMC5454720 DOI: 10.22034/apjcp.2017.18.2.295] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cisplatin (CDDP) has been widely used as a chemotherapeutic agent for solid tumors. The most common side effect of CDDP is nephrotoxicity, and many efforts have been made in the laboratory and the clinic to employ candidate adjuvants to CDDP to minimize this adverse influence. Many synthetic and herbal antioxidants as well as trace elements have been investigated for this purpose in recent years and a variety of positive and negative results have been yielded. However, no definitive supplement has so far been proposed to prevent CDDP-induced nephrotoxicity; however, this condition is gender related and the sex hormone estrogen may protect the kidney against CDDP damage. In this review, the results of research related to the effect of different synthetic and herbal antioxidants supplements are presented and discussed with suggestions included for future work.
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Affiliation(s)
- Mehdi Nematbakhsh
- Water and Electrolytes Research Center, Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran. *
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26
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Ranjbaran M, Kadkhodaee M, Seifi B. Renal tissue pro-inflammatory gene expression is reduced by erythropoietin in rats subjected to hemorrhagic shock. J Nephropathol 2016; 6:69-73. [PMID: 28491856 PMCID: PMC5418073 DOI: 10.15171/jnp.2017.12] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 11/20/2016] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Hemorrhagic shock (HS) is a condition produced by considerable loss of intravascular volume, which may eventually lead to organ damage and death. OBJECTIVES In the present study, the potential implication of the kidney tissue tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) were evaluated in the protective effects of erythropoietin (EPO) during HS. MATERIALS AND METHODS Male Wistar rats were randomized into three experimental groups; Sham, HS (hemorrhagic shock and resuscitation), and EPO (erythropoietin). HS was induced by 50% blood volume hemorrhage over 30 minutes. After 2 hours, resuscitation was performed within 30 minutes. In the EPO group, EPO (300 IU/kg, i.v.) was administered 10 minutes before HS induction. Urine was collected to determine urinary N-acetyl-β-D-glucosaminidase (NAG) activity level. The kidney cytokines (TNF-α, IL-6 and IL-10) mRNA expressions were measured by real-time polymerase chain reaction (PCR). RESULTS HS rats showed significant increase in urinary NAG activity compared to the sham group. EPO significantly attenuated the rises in urinary NAG activity compared to the HS group. In the HS animals, renal TNF-α and IL-6 mRNA expressions increased whereas no difference was observed in IL-10 mRNA expression between the HS and sham groups. EPO was able to decrease renal TNF-α and IL-6 production and increase IL-10 mRNA expression. CONCLUSIONS In this study, we demonstrated that EPO attenuates kidney damage in rats subjected to HS. The beneficial effects of EPO may be at least partly mediated by modifications in the inflammatory cascade.
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Affiliation(s)
- Mina Ranjbaran
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehri Kadkhodaee
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behjat Seifi
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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27
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Effect of Erythropoietin on Postresuscitation Renal Function in a Swine Model of Ventricular Fibrillation. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3567275. [PMID: 27847811 PMCID: PMC5099488 DOI: 10.1155/2016/3567275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 09/13/2016] [Accepted: 09/21/2016] [Indexed: 12/26/2022]
Abstract
Purpose. To investigate the effect of EPO administration on postresuscitation renal function. Methods. Twenty-four female Landrace/Large-White piglets aged 10–15 weeks with average weight of 19 ± 2 kg were randomly assigned to 2 different groups of 12 subjects each. After the end of an 8-minute ventricular fibrillation, the control group (Group C) received saline as placebo, whereas the EPO group (Group E) received EPO 5000 U/kg. The animals were resuscitated according to the 2010 European Resuscitation Council Guidelines for Resuscitation. Results. Five animals (41.67%) from Group C and 11 animals (91.67%) from Group E achieved ROSC (p = 0.027). Eight animals (66.67%, 5 surviving and 3 nonsurviving) from Group C suffered severe kidney damage or AKI compared to animals from Group E, in which none of the swine had evidence of severe kidney damage or AKI (p = 0.001). There was a statistically significant difference in all tested biochemical markers between the two groups, as well as a positive correlation of creatinine with NGAL, L-FABP, and IL-18 (summed mean values' p = 0.049, 0.01, and 0.004, resp.). Conclusions. Administration of EPO protected swine from postresuscitation acute kidney injury.
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28
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Banaei S, Ahmadiasl N, Alihemmati A. Comparison of the Protective Effects of Erythropoietin and Melatonin on Renal Ischemia-Reperfusion Injury. Trauma Mon 2016; 21:e23005. [PMID: 27921018 PMCID: PMC5124127 DOI: 10.5812/traumamon.23005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 02/11/2016] [Accepted: 02/21/2016] [Indexed: 01/16/2023] Open
Abstract
Background Renal ischemia-reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be the principal components involved in the pathophysiological tissue alterations observed during renal IR. Objectives In this study, we compared the effects of melatonin (MEL) and erythropoietin (EPO), both known antioxidant and anti-inflammatory agents, on IR-induced renal injury in rats. Materials and Methods Wistar albino rats were unilaterally nephrectomized and then subjected to 45 minutes of renal pedicle occlusion followed by 24 hours of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to the onset of ischemia. After 24 hours of reperfusion and following decapitation, blood samples were collected for the determination of the hemoglobin (Hb) and hematocrit (Hct) levels. Additionally, renal samples were taken for histological evaluation. Results Ischemia-reperfusion significantly decreased the observed Hb and Hct values. The histopathological findings in the IR group confirmed that there was an increase in the hyaline cast and thickening of the Bowman capsule basement membrane. Treatment with EPO or MEL significantly increased the Hb and Hct values. In the MEL + IR group, the histopathological changes were lower than those found in the EPO + IR group. Conclusions Treatment with EPO and MEL had a beneficial effect on renal IR injury. The results may also indicate that MEL protects against morphological damage better than EPO in renal IR injury.
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Affiliation(s)
- Shokofeh Banaei
- Department of Physiology, Ardabil University of Medical Sciences, Ardabil, IR Iran
- Corresponding author: Shokofeh Banaei, Department of Physiology, Ardabil University of Medical Sciences, Ardabil, IR Iran. Tel: +98-4512245526, E-mail:
| | - Nasser Ahmadiasl
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, IR Iran
| | - Alireza Alihemmati
- Department of Histology and Embryology, Tabriz University of Medical Sciences, Tabriz, IR Iran
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29
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Andò G, Costa F, Trio O, Oreto G, Valgimigli M. Impact of vascular access on acute kidney injury after percutaneous coronary intervention. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2016; 17:333-8. [DOI: 10.1016/j.carrev.2016.03.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/02/2016] [Accepted: 03/07/2016] [Indexed: 01/11/2023]
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30
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Heitrich M, García DMDLÁ, Stoyanoff TR, Rodríguez JP, Todaro JS, Aguirre MV. Erythropoietin attenuates renal and pulmonary injury in polymicrobial induced-sepsis through EPO-R, VEGF and VEGF-R2 modulation. Biomed Pharmacother 2016; 82:606-13. [PMID: 27470403 DOI: 10.1016/j.biopha.2016.05.045] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 05/29/2016] [Indexed: 01/04/2023] Open
Abstract
Sepsis remains the most important cause of acute kidney injury (AKI) and acute lung injury (ALI) in critically ill patients. The cecal ligation and puncture (CLP) model in experimental mice reproduces most of the clinical features of sepsis. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and pro-angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO protection through the expression of the EPO/EPO receptor (EPO-R) and VEGF/VEF-R2 systems in kidneys and lungs of mice undergoing CLP-induced sepsis. Male inbred Balb/c mice were divided in three experimental groups: Sham, CLP, and CLP+EPO (3000IU/kg sc). Assessment of renal functional parameters, survival, histological examination, immunohistochemistry and/or Western blottings of EPO-R, VEGF and VEGF-R2 were performed at 18h post-surgery. Mice demonstrated AKI by elevation of serum creatinine and renal histologic damage. EPO treatment attenuates renal dysfunction and ameliorates kidney histopathologic changes. Additionally, EPO administration attenuates deleterious septic damage in renal cortex through the overexpression of EPO-R in tubular interstitial cells and the overexpression of the pair VEGF/VEGF-R2. Similarly CLP- induced ALI, as evidenced by parenchymal lung histopathologic alterations, was ameliorated through pulmonary EPO-R, VEGF and VEGF-R2 over expression suggesting and improvement in endothelial survival and functionality. This study demonstrates that EPO exerts protective effects in kidneys and lungs in mice with CLP-induced sepsis through the expression of EPO-R and the regulation of the VEGF/VEGF-R2 pair.
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Affiliation(s)
- Mauro Heitrich
- Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina
| | - Daiana Maria de Los Ángeles García
- Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina
| | - Tania Romina Stoyanoff
- Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina
| | - Juan Pablo Rodríguez
- Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina
| | - Juan Santiago Todaro
- Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina
| | - María Victoria Aguirre
- Laboratory of Biochemical Investigations (LIBIM), School of Medicine, IQUIBA-NEA CONICET, National Northeastern University (UNNE), Argentina.
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Bidirectional signalling between EphA2 and ephrinA1 increases tubular cell attachment, laminin secretion and modulates erythropoietin expression after renal hypoxic injury. Pflugers Arch 2016; 468:1433-48. [PMID: 27228995 DOI: 10.1007/s00424-016-1838-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 05/01/2016] [Accepted: 05/10/2016] [Indexed: 10/21/2022]
Abstract
Acute kidney injury (AKI) is common in hospitalized patients and has a poor prognosis, the severity of AKI being linked to progression to chronic kidney disease. This stresses the need to search for protective mechanisms during the acute phase. We investigated kidney repair after hypoxic injury using a rat model of renal artery branch ligation, which led to an oxygen gradient vertical to the corticomedullary axis. Three distinct zones were observed: tubular necrosis, infarction border zone and preserved normal tissue. EphA2 is a receptor tyrosine kinase with pivotal roles in cell architecture, migration and survival, upon juxtacrine contact with its membrane-bound ligand EphrinA1. Following hypoxia, EphA2 was up-regulated in cortical and medullary tubular cells, while EphrinA1 was up-regulated in interstitial cells adjacent to peritubular capillaries. Moreover, erythropoietin (EPO) messenger RNA (mRNA) was strongly expressed in the border zone of infarcted kidney within the first 6 h. To gain more insight into the biological impact of EphA2 and EphrinA1 up-regulation, we activated the signalling pathways in vitro using recombinant EphrinA1/Fc or EphA2/Fc proteins. Stimulation of EphA2 forward signalling in the proximal tubular cell line HK2 increased cell attachment and laminin secretion at the baso-lateral side. Conversely, activation of reverse signalling through EphrinA1 expressed by Hep3B cells promoted EPO production at both the transcriptional and protein level. Strikingly, in co-culture experiments, juxtacrine contact between EphA2 expressing MDCK and EphrinA1 expressing Hep3B was sufficient to induce a significant up-regulation of EPO mRNA production in the latter cells, even in the absence of hypoxic conditions. The synergistic effects of EphA2 and hypoxia led to a 15-20-fold increase of EPO expression. Collectively, our results suggest an important role of EphA2/EphrinA1 signalling in kidney repair after hypoxic injury through stimulation of (i) tubular cell attachment, (ii) secretion of basal membrane proteins and (iii) EPO production. These findings could thus pave the way to new therapeutic approaches.
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32
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Ghasemi M, Nematbakhsh M, Pezeshki Z, Soltani N, Moeini M, Talebi A. Nephroprotective effect of estrogen and progesterone combination on cisplatin-induced nephrotoxicity in ovariectomized female rats. Indian J Nephrol 2016; 26:167-75. [PMID: 27194830 PMCID: PMC4862261 DOI: 10.4103/0971-4065.160337] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Recently, we reported that estrogen (Es) has no beneficial effect on cisplatin (CP)-induced nephrotoxicity, but the role of progesterone (Pr) and the combination of Es and Pr are not yet well-defined. In this study, we investigated the protective role of Pr, and co-administration of Es/Pr on CP-induced nephrotoxicity. Eighty-six ovariectomized female Wistar rats were divided into 13 groups, and the experiments were performed in two phases. In Phase I, Groups 1-4 received 2, 5, 10, and 25 mg/kg, IM Pr dissolved in sesame oil every 5 days for four doses. Groups 5-8 had the same treatment regimen as Groups 1-4, but after the third injection the animals also received continuous dose of CP (2.5 mg/kg/day, i.p.) for 8 days. Group 9, as the positive control group, received sesame oil instead of Pr plus CP. Group 10, as the negative control group, received sesame oil instead of Pr. After the most effective dose of Pr was determined in Phase I, Groups 11-13 in Phase II received 10 mg/kg Pr plus either 0.25, 0.5, or 1 mg/kg, IM estradiol valerate every 5 days for four doses. After the third injection, they also received a continuous dose of CP for 8 days. The levels of blood urea nitrogen (BUN) and creatinine (Cr), kidney tissue damage score (KTDS), and kidney weight (KW) increased and body weight (BW) decreased in the positive control group (P < 0.05). Administration of Pr (10 mg/kg) plus CP decreased KTDS and BW loss and KW. Co-administration of ES/Pr at specific doses improved Cr, BUN, and KTDS; and resulted in reduced CP-induced nephrotoxicity. The results obtained suggest that the beneficial effect of Pr on CP-induced nephrotoxicity is dose-dependent. In addition, combination of Es/Pr with a specific dose decreased CP-induced nephrotoxicity.
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Affiliation(s)
- M Ghasemi
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - M Nematbakhsh
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran; Isfahan Institute of Basic and Applied Sciences Research, Isfahan, Iran
| | - Z Pezeshki
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - N Soltani
- Department of Physiology, Hormozgan University of Medical Sciences, Isfahan, Iran
| | - M Moeini
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - A Talebi
- Department of Clinical Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
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Saad A, Herrmann SM, Textor SC. Chronic renal ischemia in humans: can cell therapy repair the kidney in occlusive renovascular disease? Physiology (Bethesda) 2016; 30:175-82. [PMID: 25933818 DOI: 10.1152/physiol.00065.2013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Occlusive renovascular disease caused by atherosclerotic renal artery stenosis (ARAS) elicits complex biological responses that eventually lead to loss of kidney function. Recent studies indicate a complex interplay of oxidative stress, endothelial dysfunction, and activation of fibrogenic and inflammatory cytokines as a result of atherosclerosis, hypoxia, and renal hypoperfusion in this disorder. Human studies emphasize the limits of the kidney adaptation to reduced blood flow, eventually leading to renal hypoxia with activation of inflammatory and fibrogenic pathways. Several randomized prospective clinical trials show that stent revascularization alone in patients with atherosclerotic renal artery stenosis provides little additional benefit to medical therapy once these processes have developed and solidified. Experimental data now support developing adjunctive cell-based measures to support angiogenesis and anti-inflammatory renal repair mechanisms. These data encourage the study of endothelial progenitor cells and/or mesenchymal stem/stromal cells for the repair of damaged kidney tissue.
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Affiliation(s)
- Ahmed Saad
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Sandra M Herrmann
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Stephen C Textor
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
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Han F, Wang O, Cai Q. Anti-apoptotic treatment in mouse models of age-related hearing loss. J Otol 2016; 11:7-12. [PMID: 29937804 PMCID: PMC6002598 DOI: 10.1016/j.joto.2016.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 03/22/2016] [Accepted: 03/24/2016] [Indexed: 01/05/2023] Open
Abstract
Age-related hearing loss (AHL), or presbycusis, is the most common neurodegenerative disorder and top communication deficit of the aged population. Genetic predisposition is one of the major factors in the development of AHL. Generally, AHL is associated with an age-dependent loss of sensory hair cells, spiral ganglion neurons and stria vascularis cells in the inner ear. Although the mechanisms leading to genetic hearing loss are not completely understood, caspase-family proteases function as important signals in the inner ear pathology. It is now accepted that mouse models are the best tools to study the mechanism of genetic hearing loss or AHL. Here, we provide a brief review of recent studies on hearing improvement in mouse models of AHL by anti-apoptotic treatment.
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Affiliation(s)
- Fengchan Han
- Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, PR China
- Institute of Neurobiology, School of Special Education, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, PR China
- Corresponding author. Key Laboratory for Genetic Hearing Disorders in Shandong, and Institute of Neurobiology, School of Special Education, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, PR China.
| | - Oumei Wang
- Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, PR China
- Institute of Neurobiology, School of Special Education, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, PR China
| | - Quanxiang Cai
- Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, PR China
- Institute of Neurobiology, School of Special Education, Binzhou Medical University, 346 Guanhai Road, Yantai 264003, Shandong, PR China
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Hussein AM, Eldosoky M, Handhle A, Elserougy H, Sarhan M, Sobh MA, Hussiny ME, El Nashar EM. Effects of long-acting erythropoietin analog darbepoetin-α on adriamycin-induced chronic nephropathy. Int Urol Nephrol 2016; 48:287-297. [PMID: 26660954 DOI: 10.1007/s11255-015-1171-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 11/21/2015] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To study the effects of darbepoetin-α (DPO-α) (erythropoietin analog) on adriamycin (ADR)-induced chronic nephropathy in rats. METHODS Sixty-nine male Sprague-Dawley rats divided into 3 groups (23 rats each): negative control group: normal rats received saline as a vehicle; positive control (ADR) group: rats received 2 iv injection of ADR via penile vein at 14-day interval without treatment; and DPO-α group: as ADR group but rats received sc DPO-α (0.3 μg/kg bw) once weekly for 12 weeks. By the end of experiment hemoglobin (Hb) content, serum creatinine, BUN, albumin, triglycerides and cholesterol, urinary protein excretion and kidney injury molecule-1 (KIM-1). GSH, malondialdehyde, caspase-3 expression histopathological and electron microscopic examinations for kidney tissues were done. RESULTS DPO-α significantly improved the animal survival rate and body weight, Hb, serum BUN, triglycerides, cholesterol, and albumin and urinary protein excretion and KIM-1 in urine. Also, administration of DPO-α improved the morphological damage in glomeruli and renal tubules as well as caspase-3 expression and markers of oxidative stress in kidney tissues. CONCLUSION Administration of DPO-α alleviates ADR nephropathy and this might due to improvement of Hb content, hyperlipidemia, enhancement of endogenous antioxidants, reduction of apoptosis and tubulointerstitial injury and maintaining the integrity of glomerular membrane.
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Affiliation(s)
- Abdelaziz M Hussein
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Mohamed Eldosoky
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Handhle
- Medical Biochemistry Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hanaa Elserougy
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed Sarhan
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed A Sobh
- Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mahmoud El Hussiny
- Medical Experimental Research Center, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman M El Nashar
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha, Egypt
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Cakiroglu F, Enders-Comberg SM, Pagel H, Rohwedel J, Lehnert H, Kramer J. Erythropoietin-enhanced endothelial progenitor cell recruitment in peripheral blood and renal vessels during experimental acute kidney injury in rats. Cell Biol Int 2016; 40:298-307. [PMID: 26616141 DOI: 10.1002/cbin.10566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 11/23/2015] [Indexed: 12/22/2022]
Abstract
Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose, rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading, and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application, there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels.
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Affiliation(s)
- Figen Cakiroglu
- Department of Internal Medicine I, Division of Nephrology and Transplantation Unit, University of Lübeck, Lübeck, Germany.,Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany
| | - Sora Maria Enders-Comberg
- Department of Internal Medicine I, Division of Nephrology and Transplantation Unit, University of Lübeck, Lübeck, Germany
| | - Horst Pagel
- Institute of Physiology, University of Lübeck, Lübeck, Germany
| | - Jürgen Rohwedel
- Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany
| | - Hendrik Lehnert
- Department of Internal Medicine I, Division of Nephrology and Transplantation Unit, University of Lübeck, Lübeck, Germany
| | - Jan Kramer
- Department of Internal Medicine I, Division of Nephrology and Transplantation Unit, University of Lübeck, Lübeck, Germany.,Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany
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Chilton J, Wilcox A, Lammey M, Meyer D. Characterization of a Cardiorenal-like Syndrome in Aged Chimpanzees (Pan troglodytes). Vet Pathol 2016; 53:417-24. [PMID: 26792841 DOI: 10.1177/0300985815618435] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Cardiorenal syndrome involves disease and dysfunction of the heart that leads to progressive renal dysfunction. This study investigated the relationship between cardiac and renal disease in 91 aged chimpanzees at the Alamogordo Primate Facility by evaluation of the medical histories, metabolic parameters, functional measurements of the cardiovascular system, clinical pathology, and histopathology focused on the heart and kidney. Cardiac fibrosis was the most frequent microscopic finding in 82 of 91 animals (90%), followed by glomerulosclerosis with tubulointerstitial fibrosis in 63 of 91 (69%). Cardiac fibrosis with attendant glomerulosclerosis and tubulointerstitial fibrosis was observed in 58 of 91 animals (63%); there was a statistically significant association between the 2 conditions. As the severity of cardiac fibrosis increased, there was corresponding increase in severity of glomerulosclerosis with tubulointerstitial fibrosis. Altered metabolic, cardiovascular, and clinical pathology parameters indicative of heart and kidney failure were commonly associated with the moderate to severe microscopic changes, and concurrent heart and kidney failure were considered the cause of death. The constellation of findings in the chimpanzees were similar to cardiorenal syndrome in humans.
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Affiliation(s)
| | | | - M Lammey
- Alamogordo Primate Facility, Alamogordo, NM, USA
| | - D Meyer
- Charles River, Reno, NV, USA
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Kapitsinou PP, Haase VH. Molecular mechanisms of ischemic preconditioning in the kidney. Am J Physiol Renal Physiol 2015; 309:F821-34. [DOI: 10.1152/ajprenal.00224.2015] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 08/21/2015] [Indexed: 12/26/2022] Open
Abstract
More effective therapeutic strategies for the prevention and treatment of acute kidney injury (AKI) are needed to improve the high morbidity and mortality associated with this frequently encountered clinical condition. Ischemic and/or hypoxic preconditioning attenuates susceptibility to ischemic injury, which results from both oxygen and nutrient deprivation and accounts for most cases of AKI. While multiple signaling pathways have been implicated in renoprotection, this review will focus on oxygen-regulated cellular and molecular responses that enhance the kidney's tolerance to ischemia and promote renal repair. Central mediators of cellular adaptation to hypoxia are hypoxia-inducible factors (HIFs). HIFs play a crucial role in ischemic/hypoxic preconditioning through the reprogramming of cellular energy metabolism, and by coordinating adenosine and nitric oxide signaling with antiapoptotic, oxidative stress, and immune responses. The therapeutic potential of HIF activation for the treatment and prevention of ischemic injuries will be critically examined in this review.
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Affiliation(s)
- Pinelopi P. Kapitsinou
- Departments of Medicine, Anatomy and Cell Biology, and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
| | - Volker H. Haase
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and
- Medicine and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee
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Hatcher HC, Tesfay L, Torti SV, Torti FM. Cytoprotective Effect of Ferritin H in Renal Ischemia Reperfusion Injury. PLoS One 2015; 10:e0138505. [PMID: 26379029 PMCID: PMC4574775 DOI: 10.1371/journal.pone.0138505] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 08/31/2015] [Indexed: 01/08/2023] Open
Abstract
Oxidative stress is a major contributor to kidney injury following ischemia reperfusion. Ferritin, a highly conserved iron-binding protein, is a key protein in the maintenance of cellular iron homeostasis and protection from oxidative stress. Ferritin mitigates oxidant stress by sequestering iron and preventing its participation in reactions that generate reactive oxygen species. Ferritin is composed of two subunit types, ferritin H and ferritin L. Using an in vivo model that enables conditional tissue-specific doxycycline-inducible expression of ferritin H in the mouse kidney, we tested the hypothesis that an increased level of H-rich ferritin is renoprotective in ischemic acute renal failure. Prior to induction of ischemia, doxycycline increased ferritin H in the kidneys of the transgenic mice nearly 6.5-fold. Following reperfusion for 24 hours, induction of neutrophil gelatinous-associated lipocalin (NGAL, a urine marker of renal dysfunction) was reduced in the ferritin H overexpressers compared to controls. Histopathologic examination following ischemia reperfusion revealed that ferritin H overexpression increased intact nuclei in renal tubules, reduced the frequency of tubular profiles with luminal cast materials, and reduced activated caspase-3 in the kidney. In addition, generation of 4-hydroxy 2-nonenal protein adducts, a measurement of oxidant stress, was decreased in ischemia-reperfused kidneys of ferritin H overexpressers. These studies demonstrate that ferritin H can inhibit apoptotic cell death, enhance tubular epithelial viability, and preserve renal function by limiting oxidative stress following ischemia reperfusion injury.
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Affiliation(s)
- Heather C. Hatcher
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Lia Tesfay
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Suzy V. Torti
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Frank M. Torti
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- * E-mail:
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The improvement of ischemia/reperfusion injury by erythropoetin is not mediated through bone marrow cell recruitment in rats. Transplant Proc 2015; 41:1113-5. [PMID: 19460493 DOI: 10.1016/j.transproceed.2009.03.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is a major cause of acute renal failure in kidney transplantation; however, the mechanisms of kidney damage and repair are not yet clear. So far no treatment has been effective to prevent I/R injury. In the present study we evaluated the effect of erythropoetin (EPO) in I/R injury in rats. We investigated the role of bone marrow cells (BMC) in kidney repair and the effect of EPO on BMC recruitment. MATERIALS AND METHODS Female Sprague Dawley rats transplanted with male BMCs underwent I/R injury. In the treatment group rats received 5000 IU of EPO 30 minutes before renal ischemia. At 2 and 4 weeks after I/R, rats were humanely killed and we measured creatinine clearance (glomerular filtration rate [GFR]), proteinuria, and body weight (BW). Renal tissue was harvested for histologic and molecular analysis. Fluorescein in situ hybridization (FISH) and TUNEL were used to determined the presence of male cell chimerism and apoptosis in renal tissue. RESULTS At 4 weeks after I/R, EPO significantly improved GFR (1.8 +/- 0.2 vs 1.2 +/- 0.14 mL/min; P < .05). No significant differences between EPO and control rats were observed in proteinuria, BW, and hemoglobin levels at 2 and 4 weeks. After death, the kidney showed only minimal tubulointerstitial changes, which were more marked in control rats. FISH analysis demonstrated a low degree of microchimerism, not significantly different between EPO and control rats. Apoptosis decreased between 2 and 4 weeks after I/R, in both EPO and control groups. CONCLUSION EPO improved GFR and injury at 4 weeks after I/R; however, it did not enhance the recruitment of BMC.
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Li YC, Chen SJ, Chien CL. Erythropoietin produced by genetic-modified NIH/3T3 fibroblasts enhances the survival of degenerating neurons. Brain Behav 2015; 5:e00356. [PMID: 26357589 PMCID: PMC4559019 DOI: 10.1002/brb3.356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 04/12/2015] [Accepted: 05/04/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Erythropoietin (EPO) has potent neuroprotective effects. The short-term delivery of high-dose EPO seemed to improve patients' neuromuscular functions; however, excessive EPO resulted in systematically high hematocrit and thrombotic risk. In our study, we established a cellular material for future in vivo studies of neurodegenerative diseases based on EPO provided regionally at a nontoxic level. METHODS A mouse EPO cDNA was subcloned into the pCMS-EGFP vector and transfected into NIH/3T3 fibroblasts to design a biological provider that can regionally release EPO for the treatment of neurological diseases. After G418 selection, a stable EPO-overexpressing cell line, EPO-3T3-EGFP, was established. To further confirm the neuroprotective abilities of secreted EPO from EPO-3T3-EGFP cells, a cell model of neurodegeneration, PC12-INT-EGFP, was applied. RESULTS The expression level of EPO was highly elevated in EPO-3T3-EGFP cells, and an abundant amount of EPO secreted from EPO-3T3-EGFP cells was detected in the extracellular milieu. After supplementation with conditioned medium prepared from EPO-3T3-EGFP cells, the survival rate of PC12-INT-EGFP cells was significantly enhanced. Surprisingly, a fraction of aggregated cytoskeletal EGFP-tagged α-internexin in PC12-INT-EGFP cells was disaggregated and transported into neurites dynamically. The immunocytochemical distribution of IF proteins, including NF-M, phosphorylated-NF-M, and the α-INT-EGFP fusion protein, were less aggregated in the perikaryal region and transported into neurites after the EPO treatment. CONCLUSION The established EPO-overexpressing NIH/3T3 cell line, EPO-3T3-EGFP, may provide a material for future studies of cell-based therapies for neurodegenerative diseases via the secretion of EPO on a short-term, high-dose, regional basis.
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Affiliation(s)
- Yi-Chin Li
- Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University Taipei, Taiwan
| | - Shiu-Jau Chen
- Department of Medicine, Mackay Medical College New Taipei, Taiwan
| | - Chung-Liang Chien
- Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University Taipei, Taiwan
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Vazquez-Mellado MJ, Aguilar C, Rocha-Zavaleta L. Erythropoietin protects neuroblastoma cells against etoposide and vincristine by activating ERK and AKT pathways but has no effect in kidney cells. Life Sci 2015; 137:142-9. [PMID: 26232556 DOI: 10.1016/j.lfs.2015.07.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 06/15/2015] [Accepted: 07/25/2015] [Indexed: 11/29/2022]
Abstract
AIMS Chemotherapy induces anaemia in neuroblastoma patients. Cancer-associated anaemia may be treated with recombinant erythropoietin. However, the potential effects of erythropoietin on neuroblastoma and kidney cells have not been extensively evaluated. The present study was designed to investigate the effect of erythropoietin on the proliferation, and protection against vincristine- and etoposide-induced cell death in neuroblastoma (MSN), and embryonic kidney (HEK 293) cells. MAIN METHODS The expression of erythropoietin and its receptor in MSN and HEK 293 was analysed by RT-PCR, immunocytochemistry, and Western blotting. The effect of erythropoietin on cell viability and proliferation was evaluated by the MTT assay, and by the Click-iT EdU Alexa Fluor 647 kit, respectively. For the cyto-protective assays, cells were incubated with erythropoietin before etoposide and vincristine treatment. Activation of signalling pathways was studied by Western blotting. KEY FINDINGS MSN and HEK 293 cells expressed the erythropoietin receptor, but not erythropoietin. Erythropoietin induced proliferation and protection against vincristine and etoposide in MSN cells. HEK 293 cells were not affected by erythropoietin. Erythropoietin showed an anti-apoptotic effect which was dependent on the activation of ERK1/2 and AKT. HEK 293 cells presented constitutively phosphorylated AKT, and showed no activation of ERK1/2 upon erythropoietin stimulation. SIGNIFICANCE These results indicate that erythropoietin induces proliferation of MSN cells, and that it can ameliorate vincristine- and etoposide-induced apoptosis of these cells. Erythropoietin-mediated neuroprotection was regulated by the combined effect of the ERK1/2 and AKT signalling pathways. Our findings provide further insights into the potential effect of erythropoietin on neuroblastoma cells.
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Affiliation(s)
- Maria Jose Vazquez-Mellado
- Departamento de Biología Molecular y Biotencología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, D.F. CP 04510, Mexico; Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Unidad de Posgrado, Edificio B Primer Piso, Ciudad Universitaria, México, D.F. CP 04510, Mexico
| | - Cecilia Aguilar
- Departamento de Biología Molecular y Biotencología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, D.F. CP 04510, Mexico
| | - Leticia Rocha-Zavaleta
- Departamento de Biología Molecular y Biotencología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, D.F. CP 04510, Mexico.
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Ramos AM, González-Guerrero C, Sanz A, Sanchez-Niño MD, Rodríguez-Osorio L, Martín-Cleary C, Fernández-Fernández B, Ruiz-Ortega M, Ortiz A. Designing drugs that combat kidney damage. Expert Opin Drug Discov 2015; 10:541-56. [PMID: 25840605 DOI: 10.1517/17460441.2015.1033394] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Kidney disease remains one of the last worldwide frontiers in the field of non-communicable human disease. From 1990 to 2013, chronic kidney disease (CKD) was the top non-communicable cause of death with a greatest increase in global years of life lost while mortality of acute kidney injury (AKI) still hovers around 50%. This reflects the paucity (for CKD) or lack of (for AKI) therapeutic approaches beyond replacing renal function. Understanding what the barriers are and what potential pathways may facilitate the design of new drugs to combat kidney disease is a key public health priority. AREAS COVERED The authors discuss the hurdles and opportunities for future drug development for kidney disease in light of experience accumulated with drugs that made it to clinical trials. EXPERT OPINION Inflammation, cell death and fibrosis are key therapeutic targets to combat kidney damage. While the specific targeting of drugs to kidney cells would be desirable, the technology is only working at the preclinical stage and with mixed success. Nanomedicines hold promise in this respect. Most drugs undergoing clinical trials for kidney disease have been repurposed from other indications. Currently, the chemokine receptor inhibitor CCX140 holds promise for CKD and the p53 inhibitor QPI-1002 for AKI.
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Affiliation(s)
- Adrián M Ramos
- Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Laboratory of Renal and Vascular Pathology and Diabetes , Av. Reyes Católicos 2, 28040, Madrid , Spain
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Kittur FS, Arthur E, Nguyen M, Hung CY, Sane DC, Xie J. Two-step purification procedure for recombinant human asialoerythropoietin expressed in transgenic plants. Int J Biol Macromol 2015; 72:1111-6. [PMID: 25450830 PMCID: PMC4260996 DOI: 10.1016/j.ijbiomac.2014.10.033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 10/13/2014] [Accepted: 10/15/2014] [Indexed: 12/19/2022]
Abstract
Asialoerythropoietin (asialo-EPO) is a desialylated form of human glycoprotein hormone erythropoietin (EPO), which has been reported to be neuro-, cardio-, and renoprotective in animal models of organ injuries. Since the current method of production of asialo-EPO from mammalian cell-made recombinant human EPO (rhuEPO(M)) by enzymatic desialylation is not commercially viable, we and others used plant-based expression systems to produce recombinant human asialo-EPO (asialo-rhuEPO(P)). Despite achieving high expression levels in plants, its purification from plant extracts has remained a greater challenge, which has prevented studying its tissue-protective effects and translating it into clinical practice. In this study, a procedure was developed to purify asialo-rhuEPO(P) from transgenic tobacco leaf tissues in two steps: ion-exchange chromatography based on its high pI (8.75) to separate it from acidic plant proteins, and immunoaffinity chromatography to obtain pure asialo-rhuEPO(P). Using this process, up to 31% of the asialo-rhuEPO(P) could be recovered to near homogeneity from plant extracts. This work demonstrates that asialo-rhuEPO(P) expressed in tobacco plants could be purified in high yield and purity using minimal steps, which might be suitable for scale-up. Furthermore, the ion-exchange chromatography step together with the use of protein-specific antibody column could be used to purify a wide variety of basic recombinant proteins from transgenic leaf tissues.
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Affiliation(s)
- Farooqahmed S Kittur
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - Elena Arthur
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - Maikhanh Nguyen
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - Chiu-Yueh Hung
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA
| | - David C Sane
- Carilion Clinic and Virginia Tech Carilion School of Medicine, Roanoke, VA 24014, USA
| | - Jiahua Xie
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute & Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
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Abstract
BACKGROUND To date, there are no known methods for preventing acute kidney injury after cardiac surgery. Increasing evidence suggests that erythropoietin has renal antiapoptotic and tissue protective effects. However, recent human studies have shown conflicting results. The authors aimed to study the effect of a single high-dose erythropoietin preoperatively on renal function after coronary artery bypass grafting in patients with preoperative impaired renal function. METHODS This single-center, randomized, double-blind, placebo-controlled study included 75 patients scheduled for coronary artery bypass grafting with preexisting renal impairment estimated glomerular filtration rate based on p-cystatin C (<60 and >15 ml/min). The patients either received a single high-dose erythropoietin (400 IU/kg) or placebo preoperatively. The primary endpoint was renal protection evaluated by p-cystatin C at the third postoperative day compared to the preoperative values. Incidence of acute kidney injury and other renal biomarker changes were among secondary endpoints. RESULTS There was no statistically significant difference on the third postoperative day for relative p-cystatin C level changes from baseline between the groups, 131 ± 31% (mean ± SD) for the study group and 125 ± 24% for the control group (P = 0.31; 95% CI, -0.6 to 20% for the difference). There were no statistically significant differences in other renal biomarkers or measures between the groups (p-neutrophil gelatinase-associated lipocalin, p-creatinine, p-urea, and estimated glomerular filtration rate). There were no other differences in outcome variables between the groups. CONCLUSION Intravenous administration of a single high-dose (400 IU/kg) erythropoietin did not have a renal protective effect on patients with reduced kidney function undergoing coronary artery bypass surgery.
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Recombinant human erythropoietin pretreatment attenuates acute renal tubular injury against ischemia-reperfusion by restoring transient receptor potential channel-6 expression and function in collecting ducts. Crit Care Med 2014; 42:e663-72. [PMID: 25072760 DOI: 10.1097/ccm.0000000000000542] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Acute renal tubular injury is a serious complication in the postoperative period, which is associated with high mortality and increased ICU stay. We aimed to demonstrate the protective effect of rhEPO against acute tubular injury induced by ischemia-reperfusion and to explore the mechanism of canonical transient receptor potential channel-6. DESIGN Randomized laboratory animal study. SETTINGS Animal research laboratory. INTERVENTIONS Male Sprague-Dawley rats were randomly divided into three groups: the sham group, the control group, and the rhEPO group. Experimental acute tubular injury was established in rats by bilateral renal arterial occlusion for 30 minutes followed by reperfusion. MEASUREMENTS AND MAIN RESULTS Blood samples were obtained for cystatin-C and neutrophil gelatinase-associated lipocalin measurements by enzyme-linked immunosorbance assays. Seventy-two hours after reperfusion, urine samples were collected for osmolality and fractional excretion of sodium (%) assays on a chemistry analyzer. Kidneys were harvested at 24, 48, and 72 hours after reperfusion. Transient receptor potential channel-6, aquaporin-2, and Na,K-ATPase expression in collecting ducts were studied by immunofluorescence and Western blot. Coimmunoprecipitations were also performed to identify the possible signalplex relation between transient receptor potential channel-6 and aquaporin-2 or Na,K-ATPase channels. RhEPO pretreatment significantly inhibited serum cystatin-C (2 hr: 453 ± 64 μg/L vs 337 ± 28 μg/L, p < 0.01), serum neutrophil gelatinase-associated lipocalin (72 hr: 1,175 ± 107 ng/L vs 1,737 ± 402 ng/L, p < 0.05), and urinary fractional excretion of sodium (%) increase (0.9 ± 0.1 vs 2.2 ± 0.8, p < 0.05) and alleviated the decrease of urinary osmolality (1,293 ± 101 mosmol/kg H2O vs 767 ± 91 mosmol/kg H2O, p < 0.05) induced by ischemia-reperfusion injury. Meanwhile, recombinant human erythropoietin greatly improved the ischemia-reperfusion-induced attenuation of transient receptor potential channel-6 expression (48 hr: 42% ± 2% vs 67% ± 2% and 72 hr: 55% ± 2% vs 66% ± 2%), as well as aquaporin-2 and Na,K-ATPase expression in collecting ducts. Transient receptor potential channel-6 functionally interacted with Na,K-ATPase but not aquaporin-2. CONCLUSIONS Recombinant human erythropoietin pretreatment at the dose of 5,000 IU/kg potently prevented ischemia-reperfusion-induced acute tubular injury, which might be partly attributed to the restoring the effect of transient receptor potential channel-6 expression and collecting duct function.
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Borovnik-Lesjak V, Whitehouse K, Baetiong A, Miao Y, Currie BM, Velmurugan S, Radhakrishnan J, Gazmuri RJ. Effects of intraosseous erythropoietin during hemorrhagic shock in swine. PLoS One 2014; 9:e110908. [PMID: 25365317 PMCID: PMC4218716 DOI: 10.1371/journal.pone.0110908] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 09/21/2014] [Indexed: 11/22/2022] Open
Abstract
Objective To determine whether erythropoietin given during hemorrhagic shock (HS) ameliorates organ injury while improving resuscitation and survival. Methods Three series of 24 pigs each were studied. In an initial series, 50% of the blood volume (BV) was removed in 30 minutes and normal saline (threefold the blood removed) started at minute 90 infusing each third in 30, 60, and 150 minutes with shed blood reinfused at minute 330 (HS-50BV). In a second series, the same HS-50BV protocol was used but removing an additional 15% of BV from minute 30 to 60 (HS-65BV). In a final series, blood was removed as in HS-65BV and intraosseous vasopressin given from minute 30 (0.04 U/kg min−1) until start of shed blood reinfusion at minute 150 (HS-65BV+VP). Normal saline was reduced to half the blood removed and given from minute 90 to 120 in half of the animals. In each series, animals were randomized 1∶1 to receive erythropoietin (1,200 U/kg) or control solution intraosseously after removing 10% of the BV. Results In HS-50BV, O2 consumption remained near baseline yielding minimal lactate increases, 88% resuscitability, and 60% survival at 72 hours. In HS-65BV, O2 consumption was reduced and lactate increased yielding 25% resuscitability. In HS-65BV+VP, vasopressin promoted hemodynamic stability yielding 92% resuscitability and 83% survival at 72 hours. Erythropoietin did not affect resuscitability or subsequent survival in any of the series but increased interleukin-10, attenuated lactate increases, and ameliorated organ injury based on lesser troponin I, AST, and ALT increases and lesser neurological deficits in the HS-65BV+VP series. Conclusions Erythropoietin given during HS in swine failed to alter resuscitability and 72 hour survival regardless of HS severity and concomitant treatment with fluids and vasopressin but attenuated acute organ injury. The studies also showed the efficacy of vasopressin and restrictive fluid resuscitation for hemodynamic stabilization and survival.
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Affiliation(s)
- Vesna Borovnik-Lesjak
- Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America
| | - Kasen Whitehouse
- Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America
| | - Alvin Baetiong
- Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America
| | - Yang Miao
- Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America
| | - Brian M. Currie
- Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America
| | - Sathya Velmurugan
- Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America
| | - Jeejabai Radhakrishnan
- Department of Medicine and Resuscitation Institute at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, United States of America
| | - Raúl J. Gazmuri
- Department of Medicine, Department of Physiology and Biophysics, and Resuscitation Institute at Rosalind Franklin University of Medicine and Science, and Critical Care Medicine at the Captain James A. Lovell Federal Health Care Center, North Chicago, Illinois, United States of America
- * E-mail:
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Le syndrome cardiorénal : diagnostic, physiopathologie et prise en charge. MEDECINE INTENSIVE REANIMATION 2014. [DOI: 10.1007/s13546-014-0897-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Parvin AA, Pranap RA, Shalini U, Devendran A, Baker JE, Dhanasekaran A. Erythropoietin protects cardiomyocytes from cell death during hypoxia/reperfusion injury through activation of survival signaling pathways. PLoS One 2014; 9:e107453. [PMID: 25237819 PMCID: PMC4169563 DOI: 10.1371/journal.pone.0107453] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 05/29/2014] [Indexed: 12/17/2022] Open
Abstract
Hypoxia/Reoxygenation (H/R) cardiac injury is of great importance in understanding Myocardial Infarctions, which affect a major part of the working population causing debilitating side effects and often-premature mortality. H/R injury primarily consists of apoptotic and necrotic death of cardiomyocytes due to a compromise in the integrity of the mitochondrial membrane. Major factors associated in the deregulation of the membrane include fluctuating reactive oxygen species (ROS), deregulation of mitochondrial permeability transport pore (MPTP), uncontrolled calcium (Ca2+) fluxes, and abnormal caspase-3 activity. Erythropoietin (EPO) is strongly inferred to be cardioprotective and acts by inhibiting the above-mentioned processes. Surprisingly, the underlying mechanism of EPO's action and H/R injury is yet to be fully investigated and elucidated. This study examined whether EPO maintains Ca2+ homeostasis and the mitochondrial membrane potential (ΔΨm) in cardiomyocytes when subjected to H/R injury and further explored the underlying mechanisms involved. H9C2 cells were exposed to different concentrations of EPO post-H/R, and 20 U/ml EPO was found to significantly increase cell viability by inhibiting the intracellular production of ROS and caspase-3 activity. The protective effect of EPO was abolished when H/R-induced H9C2 cells were treated with Wortmannin, an inhibitor of Akt, suggesting the mechanism of action through the activation Akt, a major survival pathway.
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Affiliation(s)
- Asiya A Parvin
- Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India
| | - Raj A Pranap
- Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India
| | - U Shalini
- Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India
| | - Ajay Devendran
- Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India
| | - John E Baker
- Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
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Stojanović VD, Vučković NM, Barišić NA, Srdić B, Doronjski AD, Peco Antić AE. Early biomarkers of renal injury and protective effect of erythropoietin on kidneys of asphyxiated newborn rats. Pediatr Res 2014; 76:11-6. [PMID: 24713815 DOI: 10.1038/pr.2014.50] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 01/10/2014] [Indexed: 12/31/2022]
Abstract
BACKGROUND The aims of this study were to determine which of the two biomarkers of renal injury, kidney injury molecule-1 or cystatin C, is more sensitive and to evaluate whether erythropoietin protects kidneys injured by perinatal asphyxia. METHODS Animals were split into three groups designated as follows: AE, pups that survived perinatal asphyxia and subsequently received 2.5 μg (0.1 ml) of darbepoetin-α (i.p.); A, the pups that survived perinatal asphyxia and received 0.1 ml of 0.9% NaCl; and C, control group. The pups were killed at different ages of life (6 h, 24 h, 48 h, 7 d, and 14 d of age; 10 rats in each subgroup). Immunohistopathological evaluation of kidneys was performed. RESULTS At 48 h and on days 7 and 14, absolute injury scores were significantly lower in group AE as measured by both biomarkers. Cystatin C expression was the most intensive 6 h after the hypoxic event (average value of absolute injury score was 2.82) and declined over time. Expression of kidney injury molecule-1 was less intensive, with the average value of absolute injury score being 2.02 at 6 h and 2.105 at 24 h; the peak value (2.155) was recorded 48 h after the hypoxic event. CONCLUSION Erythropoietin has a protective effect on hypoxic kidneys. Cystatin C is more sensitive as an early biomarker of acute kidney injury in comparison with kidney injury molecule-1.
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Affiliation(s)
- Vesna D Stojanović
- 1] Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia [2] Institute for Child and Youth Health Care of Vojvodina, Novi Sad, Serbia
| | - Nada M Vučković
- 1] Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia [2] Clinical Centre of Vojvodina, Centre for Pathology and Histology, Novi Sad, Serbia
| | - Nenad A Barišić
- 1] Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia [2] Institute for Child and Youth Health Care of Vojvodina, Novi Sad, Serbia
| | - Biljana Srdić
- Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Aleksandra D Doronjski
- 1] Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia [2] Institute for Child and Youth Health Care of Vojvodina, Novi Sad, Serbia
| | - Amira E Peco Antić
- 1] Department of Nephrology, University Children's Hospital, Belgrade, Serbia [2] Medical School, University of Belgrade, Belgrade, Serbia
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