{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:24:47Z","timestamp":1790882687691,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T00:00:00Z","timestamp":1605571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Sciences and Engineering Research Council","award":["RGPIN-2017-05500"],"award-info":[{"award-number":["RGPIN-2017-05500"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Patients with acute kidney injury (AKI) have an increased risk of cardiovascular disease. The underlying mechanism of AKI-induced heart injury is not well-understood. Hydrogen sulfide (H2S), at physiological concentrations, has been implicated in cardiovascular protection through redox balance and vessel relaxation. Cystathionine gamma-lyase (CSE) plays an essential role in H2S production in the heart. The present study investigated the effect of AKI on H2S production and oxidative stress in the heart. AKI was induced by kidney ischemia-reperfusion in male and female Sprague-Dawley rats, which led to an increase in plasma creatinine and blood urea nitrogen levels. There was a significant increase in lipid peroxidation and a decrease in glutathione (antioxidant) levels in the plasma and heart, indicating systemic and cardiac oxidative stress. Kidney ischemia-reperfusion reduced CSE expression and H2S production in the heart. There was a decrease in antioxidant transcription factor Nrf2 level in the nucleus and an increase in inflammatory cytokine (IL-6, TNF-\u03b1) expression in the heart. These results suggest that AKI can down-regulate CSE-mediated H2S production, reduce glutathione levels and increase oxidative stress in the heart. This may contribute to an increased risk of cardiovascular disease in AKI.<\/jats:p>","DOI":"10.3390\/biom10111565","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T11:02:12Z","timestamp":1605610932000},"page":"1565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Kidney Ischemia-Reperfusion Decreases Hydrogen Sulfide and Increases Oxidative Stress in the Heart"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6119-1320","authenticated-orcid":false,"given":"Charith U. B.","family":"Wijerathne","sequence":"first","affiliation":[{"name":"St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada"},{"name":"Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susara","family":"Madduma Hewage","sequence":"additional","affiliation":[{"name":"St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada"},{"name":"Department of Physiology &amp; Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6623-2881","authenticated-orcid":false,"given":"Yaw L.","family":"Siow","sequence":"additional","affiliation":[{"name":"St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada"},{"name":"Department of Physiology &amp; Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"},{"name":"Agriculture and Agri-Food Canada, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karmin","family":"O","sequence":"additional","affiliation":[{"name":"St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada"},{"name":"Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"},{"name":"Department of Physiology &amp; Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3389\/fmed.2020.00201","article-title":"Kidney ischemia-reperfusion elicits acute liver injury and inflammatory response","volume":"7","author":"Shang","year":"2020","journal-title":"Front. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1053\/j.ajkd.2018.03.028","article-title":"Distant organ dysfunction in acute kidney injury: A review","volume":"72","author":"Lee","year":"2018","journal-title":"Am. J. Kidney. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1161\/01.HYP.0000102971.85504.7c","article-title":"Kidney disease as a risk factor for development of cardiovascular disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention","volume":"42","author":"Sarnak","year":"2003","journal-title":"Hypertension"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"833","DOI":"10.2215\/CJN.12591117","article-title":"Acute kidney injury and risk of heart failure and atherosclerotic events","volume":"13","author":"Go","year":"2018","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2215\/CJN.05081107","article-title":"Management of cardiovascular disease in renal transplant recipients","volume":"3","author":"Shirali","year":"2008","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1124\/mol.117.111146","article-title":"Activation of Constitutive Androstane Receptor Ameliorates Renal Ischemia-Reperfusion-Induced Kidney and Liver Injury","volume":"93","author":"Choi","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrcardio.2016.185","article-title":"Inflammatory processes in cardiovascular disease: A route to targeted therapies","volume":"14","author":"Ruparelia","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/ncpcardio1211","article-title":"Oxidative stress in vascular disease: Causes, defense mechanisms and potential therapies","volume":"5","year":"2008","journal-title":"Nat. Clin. Pract. Cardiovasc. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mam.2008.08.006","article-title":"Glutathione: Overview of its protective roles, measurement, and biosynthesis","volume":"30","author":"Forman","year":"2009","journal-title":"Mol. Aspects. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5028181","DOI":"10.1155\/2019\/5028181","article-title":"Glutathione \u201credox homeostasis\u201d and its relation to cardiovascular disease","volume":"2019","author":"Bajic","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17907","DOI":"10.1073\/pnas.0709010104","article-title":"A new gaseous signaling molecule emerges: Cardioprotective role of hydrogen sulfide","volume":"104","author":"Lefer","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"925167","DOI":"10.1155\/2015\/925167","article-title":"The cardioprotective effects of hydrogen sulfide in heart diseases: From molecular mechanisms to therapeutic potential","volume":"2015","author":"Shen","year":"2015","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1161\/ATVBAHA.120.314084","article-title":"Reactive Sulfur Species: A New Redox Player in Cardiovascular Pathophysiology","volume":"40","author":"Kolluru","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3389\/fphar.2017.00007","article-title":"The new synthetic H2S-releasing SDSS protects MC3T3-E1 osteoblasts against H2O2-induced apoptosis by suppressing oxidative stress, inhibiting MAPKs, and activating the PI3K\/Akt pathway","volume":"8","author":"Yan","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15560","DOI":"10.1073\/pnas.0705891104","article-title":"Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function","volume":"104","author":"Elrod","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1093\/ndt\/gfr560","article-title":"Downregulation of the renal and hepatic hydrogen sulfide (H2S)-producing enzymes and capacity in chronic kidney disease","volume":"27","author":"Aminzadeh","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1161\/CIRCULATIONAHA.112.000855","article-title":"H2S protects against pressure overload\u2013induced heart failure via upregulation of endothelial nitric oxide synthase","volume":"127","author":"Kondo","year":"2013","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1126\/science.1162667","article-title":"H2S as a physiologic vasorelaxant: Hypertension in mice with deletion of cystathionine \u03b3-lyase","volume":"322","author":"Yang","year":"2008","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Corsello, T., Komaravelli, N., and Casola, A. (2018). Role of hydrogen sulfide in NRF2-and sirtuin-dependent maintenance of cellular redox balance. Antioxidants, 7.","DOI":"10.3390\/antiox7100129"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1152\/physiolgenomics.00041.2017","article-title":"Nrf2 at the heart of oxidative stress and cardiac protection","volume":"50","author":"Chen","year":"2018","journal-title":"Physiol. Genom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1161\/ATVBAHA.109.193375","article-title":"Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state","volume":"29","author":"Zakkar","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1016\/j.bbadis.2014.06.002","article-title":"Myocardial ischemic reperfusion induces de novo Nrf2 protein translation","volume":"1842","author":"Xu","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Donnarumma, E., Bhushan, S., Bradley, J.M., Otsuka, H., Donnelly, E.L., Lefer, D.J., and Islam, K.N. (2016). Nitrite therapy ameliorates myocardial dysfunction via H2S and nuclear factor-erythroid 2-related factor 2 (Nrf2)-dependent signaling in chronic heart failure. J. Am. Heart Assoc., 5.","DOI":"10.1161\/JAHA.116.003551"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/ki.2011.241","article-title":"The distant organ effects of acute kidney injury","volume":"81","author":"Grams","year":"2012","journal-title":"Kidney Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"F1354","DOI":"10.1152\/ajprenal.00301.2006","article-title":"Detrimental role of homocysteine in renal ischemia-reperfusion injury","volume":"292","author":"Prathapasinghe","year":"2007","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18225","DOI":"10.1074\/jbc.M110.132142","article-title":"Ischemia\/reperfusion reduces transcription factor Sp1-mediated cystathionine \u03b2-synthase expression in the kidney","volume":"285","author":"Wu","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"F27","DOI":"10.1152\/ajprenal.00096.2009","article-title":"Ischemia-reperfusion reduces cystathionine-\u03b2-synthase-mediated hydrogen sulfide generation in the kidney","volume":"297","author":"Xu","year":"2009","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, P., Isaak, C., Siow, Y., and O, K. (2014). Downregulation of cystathionine b-synthase and cystathionine c-lyase expression stimulates inflammation in kidney ischemia-reperfusion injury. Physiol. Rep., 2.","DOI":"10.14814\/phy2.12251"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9707292","DOI":"10.1155\/2016\/9707292","article-title":"Downregulation of glutathione biosynthesis contributes to oxidative stress and liver dysfunction in acute kidney injury","volume":"2016","author":"Shang","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1042\/bj2060267","article-title":"Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat","volume":"206","author":"Stipanuk","year":"1982","journal-title":"Biochem. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"F912","DOI":"10.1152\/ajprenal.00040.2008","article-title":"Inhibition of cystathionine-\u03b2-synthase activity during renal ischemia-reperfusion: Role of pH and nitric oxide","volume":"295","author":"Prathapasinghe","year":"2008","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/nrcardio.2014.189","article-title":"Mitochondrial dysfunction and oxidative stress in CHF","volume":"12","author":"Okonko","year":"2015","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_33","first-page":"1091","article-title":"Redox signaling in cardiac physiology and pathology","volume":"111","author":"Burgoyne","year":"2012","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3389\/fphys.2013.00042","article-title":"Cytokine-induced oxidative stress in cardiac inflammation and heart failure\u2014How the ubiquitin proteasome system targets this vicious cycle","volume":"4","author":"Voigt","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1016\/j.transproceed.2013.09.006","article-title":"Curcumin Treatment Protects Against Renal Ischemia and Reperfusion Injury\u2013Induced Cardiac Dysfunction and Myocardial Injury","volume":"45","author":"Chen","year":"2013","journal-title":"Transplant. Proc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.pharep.2019.06.007","article-title":"Protective effects of naringin and trimetazidine on remote effect of acute renal injury on oxidative stress and myocardial injury through Nrf-2 regulation","volume":"71","author":"Amini","year":"2019","journal-title":"Pharmacol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40635-014-0028-8","article-title":"Effects of atrial natriuretic peptide on inter-organ crosstalk among the kidney, lung, and heart in a rat model of renal ischemia-reperfusion injury","volume":"2","author":"Mitaka","year":"2014","journal-title":"Intensive Care Med. Exp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1161\/01.CIR.80.6.1795","article-title":"Relation between myocardial glutathione content and extent of ischemia-reperfusion injury","volume":"80","author":"Singh","year":"1989","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Damy, T., Kirsch, M., Khouzami, L., Caramelle, P., Le Corvoisier, P., Roudot-Thoraval, F., Dubois-Rand\u00e9, J.-L., Hittinger, L., Pavoine, C., and Pecker, F. (2009). Glutathione deficiency in cardiac patients is related to the functional status and structural cardiac abnormalities. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004871"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1006\/jmcc.2000.1203","article-title":"Glutathione protects against myocardial ischemia\u2013reperfusion injury by detoxifying peroxynitrite","volume":"32","author":"Cheung","year":"2000","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.kint.2018.10.020","article-title":"Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice","volume":"95","author":"Fox","year":"2019","journal-title":"Kidney Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"42483","DOI":"10.1074\/jbc.M111.304592","article-title":"Altered glutathione homeostasis in heart augments cardiac lipotoxicity associated with diet-induced obesity in mice","volume":"286","author":"Ghosh","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1681\/ASN.2012030268","article-title":"Cystathionine gamma-lyase protects against renal ischemia\/reperfusion by modulating oxidative stress","volume":"24","author":"Bos","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11010-011-1044-6","article-title":"Nitric oxide synthase inhibition abrogates hydrogen sulfide-induced cardioprotection in mice","volume":"360","author":"Sojitra","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1161\/CIRCRESAHA.109.199919","article-title":"Hydrogen sulfide mediates cardioprotection through Nrf2 signaling","volume":"105","author":"Calvert","year":"2009","journal-title":"Circ. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1016\/j.febslet.2005.04.058","article-title":"Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: Protection against reactive oxygen and nitrogen species-induced cell injury","volume":"579","author":"Zhu","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1089\/ars.2012.4645","article-title":"Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2","volume":"18","author":"Yang","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1089\/ars.2012.4944","article-title":"The gasotransmitter hydrogen sulfide induces nrf2-target genes by inactivating the keap1 ubiquitin ligase substrate adaptor through formation of a disulfide bond between cys-226 and cys-613","volume":"19","author":"Hourihan","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1161\/01.CIR.95.1.252","article-title":"Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture","volume":"95","year":"1997","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.physiol.010908.163156","article-title":"Sex-based cardiac physiology","volume":"71","author":"Luczak","year":"2009","journal-title":"Annu. Rev. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0140-6736(20)30543-2","article-title":"Variations between women and men in risk factors, treatments, cardiovascular disease incidence, and death in 27 high-income, middle-income, and low-income countries (PURE): A prospective cohort study","volume":"396","author":"Joseph","year":"2020","journal-title":"Lancet"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1565\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:34:38Z","timestamp":1760178878000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/11\/1565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,17]]},"references-count":51,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["biom10111565"],"URL":"https:\/\/doi.org\/10.3390\/biom10111565","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,17]]}}}