{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:31:32Z","timestamp":1792801892138,"version":"4.5.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Chronic kidney disease (CKD) is often accompanied by dyslipidemia, and abnormal lipid metabolism in proximal tubule cells is considered closely related to the dysfunction of proximal tubule cells and eventually leads to accelerated kidney damage. Nuclear factor E2-related factor 2 (Nrf2), known as a redox-sensitive transcription factor, is responsible for regulating cellular redox homeostasis. However, the exact role of Nrf2 in dyslipidemia-induced dysfunction of proximal tubule cells is still not fully elucidated. In the present study, we showed that palmitic acid (PA) induced mitochondrial damage, excessive mitochondrial reactive oxygen species (ROS) (mtROS) generation, and cell injury in HK-2 cells. We further found that mtROS generation was involved in PA-induced mitochondrial dysfunction, cytoskeletal damage, and cell apoptosis in HK-2 cells. In addition, we demonstrated that the Nrf2\/ARE signaling pathway was activated in PA-induced HK-2 cells and that silencing Nrf2 dramatically aggravated PA-induced mtROS production, mitochondrial damage, cytoskeletal damage and cell apoptosis in HK-2 cells. However, the mitochondrial antioxidant MitoTEMPOL effectively eliminated these negative effects of Nrf2 silencing in HK-2 cells under PA stimulation. Moreover, activation of the Nrf2\/ARE signaling pathway with tBHQ attenuated renal injury, significantly reduced mtROS generation, and improved mitochondrial function in rats with HFD-induced obesity. Taken together, these results suggest that the Nrf2\/ARE-mediated antioxidant response plays a protective role in hyperlipidemia-induced renal injury by ameliorating mtROS-mediated mitochondrial dysfunction and that enhancing Nrf2 antioxidant signaling provides a potential therapeutic strategy for kidney injury in CKD with hyperlipidemia.<\/jats:p>","DOI":"10.3389\/fmed.2022.939149","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T04:29:01Z","timestamp":1663043341000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Activation of the Nrf2\/ARE signaling pathway protects against palmitic acid-induced renal tubular epithelial cell injury by ameliorating mitochondrial reactive oxygen species-mediated mitochondrial dysfunction"],"prefix":"10.3389","volume":"9","author":[{"given":"Xu-shun","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-yao","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun-jia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-li","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-feng","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-gang","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.5551\/jat.12849","article-title":"Lipid abnormalities in patients with chronic kidney disease: implications for the pathophysiology of atherosclerosis.","volume":"20","author":"Keane","year":"2013","journal-title":"J Atheroscler Thromb."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1681\/asn.2006091006","article-title":"Lipoprotein metabolism and lipid management in chronic kidney disease.","volume":"18","author":"Kwan","year":"2007","journal-title":"J Am Soc Nephrol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.14670\/hh-26.1599","article-title":"Mechanisms and consequences of hypertriglyceridemia and cellular lipid accumulation in chronic kidney disease and metabolic syndrome.","volume":"26","author":"Lee","year":"2011","journal-title":"Histol Histopathol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"c148","DOI":"10.1159\/000214210","article-title":"Urinary fatty acids and liver-type fatty acid binding protein in diabetic nephropathy.","volume":"112","author":"Sasaki","year":"2009","journal-title":"Nephron Clin Pract."},{"key":"B5","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/s2213-8587(14)70065-8","article-title":"Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease.","volume":"2","author":"de Vries","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.molmed.2004.09.003","article-title":"Nrf2-Keap1 defines a physiologically important stress response mechanism.","volume":"10","author":"Motohashi","year":"2004","journal-title":"Trends Mol Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1016\/j.tips.2013.04.005","article-title":"Toward clinical application of the Keap1-Nrf2 pathway.","volume":"34","author":"Suzuki","year":"2013","journal-title":"Trends Pharmacol Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.tibs.2014.02.002","article-title":"The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.","volume":"39","author":"Hayes","year":"2014","journal-title":"Trends Biochem Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.mrfmmm.2009.09.007","article-title":"Protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders.","volume":"690","author":"Kim","year":"2010","journal-title":"Mutat Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.biopha.2015.03.008","article-title":"Chemopreventive role of anthocyanins in atherosclerosis via activation of Nrf2-are as an indicator and modulator of redox.","volume":"72","author":"Aboonabi","year":"2015","journal-title":"Biomed Pharmacother."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/9237263","article-title":"The role of Nrf2 in cardiovascular function and disease.","volume":"2017","author":"Satta","year":"2017","journal-title":"Oxid Med Cell Longev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1089\/ars.2008.2242","article-title":"The Nrf2\/are pathway as a potential therapeutic target in neurodegenerative disease.","volume":"11","author":"Calkins","year":"2009","journal-title":"Antioxid Redox Signal."},{"key":"B13","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1111\/apha.12164","article-title":"Activation of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) and Nrf-2-dependent genes by ischaemic pre-conditioning and post-conditioning: new adaptive endogenous protective responses against renal ischaemia\/reperfusion injury.","volume":"210","author":"Shokeir","year":"2014","journal-title":"Acta Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/ki.2009.157","article-title":"Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice.","volume":"76","author":"Liu","year":"2009","journal-title":"Kidney Int."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1038\/ki.2012.439","article-title":"Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease.","volume":"83","author":"Ruiz","year":"2013","journal-title":"Kidney Int."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/3797802","article-title":"Role of nuclear factor erythroid 2-related factor 2 in diabetic nephropathy.","volume":"2017","author":"Cui","year":"2017","journal-title":"J Diabetes Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1111\/j.1365-2443.2008.01234.x","article-title":"Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice.","volume":"13","author":"Yoh","year":"2008","journal-title":"Genes Cells."},{"key":"B18","doi-asserted-by":"publisher","first-page":"850","DOI":"10.2337\/db09-1342","article-title":"The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy.","volume":"59","author":"Jiang","year":"2010","journal-title":"Diabetes."},{"key":"B19","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.mad.2010.07.003","article-title":"Signaling pathways in mitochondrial dysfunction and aging.","volume":"131","author":"Mammucari","year":"2010","journal-title":"Mech Ageing Dev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1158\/1078-0432.CCR-08-0144","article-title":"Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy.","volume":"15","author":"Kang","year":"2009","journal-title":"Clin Cancer Res."},{"key":"B21","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/S0140-6736(82)91513-6","article-title":"Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease.","volume":"2","author":"Moorhead","year":"1982","journal-title":"Lancet."},{"key":"B22","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1681\/ASN.V114669","article-title":"Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats.","volume":"11","author":"Joles","year":"2000","journal-title":"J Am Soc Nephrol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1152\/physrev.1986.66.2.469","article-title":"Renal substrate metabolism.","volume":"66","author":"Wirthensohn","year":"1986","journal-title":"Physiol Rev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"R551","DOI":"10.1016\/j.cub.2006.06.054","article-title":"Mitochondria: more than just a powerhouse.","volume":"16","author":"McBride","year":"2006","journal-title":"Curr Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.redox.2014.11.006","article-title":"Mitochondrial dynamics and mitochondrial quality control.","volume":"4","author":"Ni","year":"2015","journal-title":"Redox Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1016\/j.apsb.2020.03.004","article-title":"Mitochondrial quality control mechanisms as molecular targets in cardiac ischemia-reperfusion injury.","volume":"10","author":"Wang","year":"2020","journal-title":"Acta Pharm Sin B."},{"key":"B27","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1161\/CIRCULATIONAHA.110.014506","article-title":"Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus.","volume":"124","author":"Shenouda","year":"2011","journal-title":"Circulation."},{"key":"B28","doi-asserted-by":"publisher","first-page":"3851","DOI":"10.2337\/db13-0039","article-title":"Peptide activates ampkalpha and prevents ros-mediated mitochondrial fission and endothelial apoptosis in diabetes.","volume":"62","author":"Bhatt","year":"2013","journal-title":"Diabetes."},{"key":"B29","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.molcel.2008.02.005","article-title":"Chemical inhibitor of Drp1 uncouples mitochondrial fission and apoptosis.","volume":"29","author":"Tanaka","year":"2008","journal-title":"Mol Cell."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2019.101415","article-title":"Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic aki via suppression of Drp1-mediated mitochondrial fission.","volume":"30","author":"Wang","year":"2020","journal-title":"Redox Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/s10456-020-09720-2","article-title":"New insights into the role of mitochondria in cardiac microvascular ischemia\/reperfusion injury.","volume":"23","author":"Wang","year":"2020","journal-title":"Angiogenesis."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/s12986-015-0044-z","article-title":"Mitochondria: a new therapeutic target in chronic kidney disease.","volume":"12","author":"Granata","year":"2015","journal-title":"Nutr Metab."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-017-0710-9","article-title":"Role of mitochondrial dysfunction in hypertension and obesity.","volume":"19","author":"Lahera","year":"2017","journal-title":"Curr Hypertens Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"F731","DOI":"10.1152\/ajprenal.00188.2015","article-title":"Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin.","volume":"309","author":"Munusamy","year":"2015","journal-title":"Am J Physiol Renal Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1016\/j.kint.2016.06.013","article-title":"Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury.","volume":"90","author":"Szeto","year":"2016","journal-title":"Kidney Int."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104771","article-title":"Mitochondrial quality control in cardiac microvascular ischemia-reperfusion injury: new insights into the mechanisms and therapeutic potentials.","volume":"156","author":"Wang","year":"2020","journal-title":"Pharmacol Res."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5153268","article-title":"Reactive oxygen species and Nrf2: functional and transcriptional regulators of hematopoiesis.","volume":"2019","author":"Hu","year":"2019","journal-title":"Oxid Med Cell Longev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2996","DOI":"10.1128\/MCB.00225-13","article-title":"The Keap1-Nrf2 system prevents onset of diabetes mellitus.","volume":"33","author":"Uruno","year":"2013","journal-title":"Mol Cell Biol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/4657651","article-title":"Tert-Butylhydroquinone treatment alleviates contrast-induced nephropathy in rats by activating the Nrf2\/Sirt3\/Sod2 signaling pathway.","volume":"2019","author":"Zhou","year":"2019","journal-title":"Oxid Med Cell Longev."},{"key":"B40","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.cotox.2016.10.002","article-title":"The multifaceted role of Nrf2 in mitochondrial function.","volume":"1","author":"Holmstr\u00f6m","year":"2016","journal-title":"Curr Opin Toxicol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.redox.2016.12.022","article-title":"The mitochondria-targeted antioxidant Mitoq ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2\/Pink1.","volume":"11","author":"Xiao","year":"2017","journal-title":"Redox Biol."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.939149\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T04:29:14Z","timestamp":1663043354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.939149\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,13]]},"references-count":41,"alternative-id":["10.3389\/fmed.2022.939149"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.939149","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,13]]},"article-number":"939149"}}