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(Landmark Ed)"],"abstract":"<jats:p>Background: Dexmedetomidine (DEX) reportedly protects against ischemia-reperfusion (I\/R) injury and associated damage to the kidneys, but the underlying mechanisms have yet to be established. Methods: Unilateral nephrectomy was performed in Wistar rats, and the remaining kidney was clamped for 1 h prior to reperfusion to establish an experimental model system. These animals were then randomized into Sham, DEX + Sham, DEX + I\/R, ATI (Altepamizole, \u03b12-adrenergic receptor inhibitor) + DEX + I\/R, and 3-MA (3-methyladenine, autophagy inhibitor) + DEX + I\/R groups. Serum renal function biomarkers, acute kidney injury (AKI) histopathological scores, serum inflammatory factors, redox biomarkers, markers of autophagic flux, and autophagosome numbers were assessed. Levels of proteins related to the autophagic pathway, including mTOR and AMPK, were also analyzed. Results: Serum creatinine and urea nitrogen levels in the I\/R group were significantly elevated over those in sham control rats, as were AKI scores, serum inflammatory cytokine concentrations (IL-6, IL-1\u03b2, and TNF-\u03b1), and serum levels of the oxidative stress biomarker malondialdehyde (MDA). All of these parameters were significantly reduced in the DEX + I\/R group relative to I\/R model rats. I\/R group rats also exhibited significant decreases in renal levels of autophagic flux-related biomarkers and autophagosome numbers relative to sham controls, while DEX administration partially restored normal autophagic flux in these rats. Acute I\/R also suppress the expression of AMPK in the kidney while increasing mTOR expression, and DEX reversed these effects. The beneficial impact of DEX on I\/R-associated AKI was ablated by ATI or 3-MA administration. Conclusions: These analyses provide strong evidence for the ability of DEX to protect against I\/R-associated AKI via the \u03b12-AR\/AMPK\/mTOR pathway-mediated enhancement of autophagic activity.<\/jats:p>","DOI":"10.31083\/j.fbl2812323","type":"journal-article","created":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T08:19:27Z","timestamp":1701418767000},"source":"Crossref","is-referenced-by-count":19,"title":["Dexmedetomidine Alleviates Ischemia\/Reperfusion-Associated Acute Kidney Injury by Enhancing Autophagic Activity via the \u03b12-AR\/AMPK\/mTOR Pathway"],"prefix":"10.31083","volume":"28","author":[{"given":"Bi-Ying","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 215008 Suzhou, Jiangsu, China"},{"name":"Suzhou Clinical Medical Center of Critical Care Medicine, 215001 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital of Soochow University, 215006 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Rui","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 215008 Suzhou, Jiangsu, China"},{"name":"Suzhou Clinical Medical Center of Critical Care Medicine, 215001 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Lin","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 215008 Suzhou, Jiangsu, China"},{"name":"Suzhou Clinical Medical Center of Critical Care Medicine, 215001 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Tian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Physiology and Neurosciences, Medical College of Soochow University, 215123 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Xiang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 215008 Suzhou, Jiangsu, China"},{"name":"Suzhou Clinical Medical Center of Critical Care Medicine, 215001 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Xing","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Physiology and Neurosciences, Medical College of Soochow University, 215123 Suzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2023,12,1]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Ronco C, Bellomo R, Kellum JA. Acute kidney injury. The Lancet. 2019; 394: 1949\u20131964.","DOI":"10.1016\/S0140-6736(19)32563-2"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Linville RM, Sklar MB, Grifno GN, Nerenberg RF, Zhou J, Ye R, et al. Three-dimensional microenvironment regulates gene expression, function, and tight junction dynamics of iPSC-derived blood-brain barrier microvessels. Fluids and Barriers of the CNS. 2022; 19: 87.","DOI":"10.1186\/s12987-022-00377-1"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Wiersema R, Eck RJ, Haapio M, Koeze J, Poukkanen M, Keus F, et al. Burden of acute kidney injury and 90-day mortality in critically ill patients. BMC Nephrology. 2020; 21: 1.","DOI":"10.1186\/s12882-019-1645-y"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute Kidney Injury and Chronic Kidney Disease as Interconnected Syndromes. New England Journal of Medicine. 2014; 371: 58\u201366.","DOI":"10.1056\/NEJMra1214243"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Thiele RH, Isbell JM, Rosner MH. AKI Associated with Cardiac Surgery. Clinical Journal of the American Society of Nephrology. 2015; 10: 500\u2013514.","DOI":"10.2215\/CJN.07830814"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Tian R, Wang P, Huang L, Li C, Lu Z, Lu Z, et al. Sanqi Oral Solution Ameliorates Renal Ischemia\/Reperfusion Injury via Reducing Apoptosis and Enhancing Autophagy: Involvement of ERK\/mTOR Pathways. Frontiers in Pharmacology. 2020; 11: 537147.","DOI":"10.3389\/fphar.2020.537147"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Higashi T, Saito AC, Fukazawa Y, Furuse M, Higashi AY, Ono M, et al. EpCAM proteolysis and release of complexed claudin-7 repair and maintain the tight junction barrier. Journal of Cell Biology. 2023; 222: e202204079.","DOI":"10.1083\/jcb.202204079"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Reid S, Scholey JW. Recent Approaches to Targeting Canonical NF\u03baB Signaling in the Early Inflammatory Response to Renal IRI. Journal of the American Society of Nephrology. 2021; 32: 2117\u20132124.","DOI":"10.1681\/ASN.2021010069"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Khajuria A, Tay C, Shi J, Zhao H, Ma D. Anesthetics attenuate ischemia-reperfusion induced renal injury: effects and mechanisms. Acta Anaesthesiologica Taiwanica. 2014; 52: 176\u2013184.","DOI":"10.1016\/j.aat.2014.10.001"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Wu Y, Qiu G, Zhang H, Zhu L, Cheng G, Wang Y, et al. Dexmedetomidine alleviates hepatic ischaemia-reperfusion injury via the PI3K\/AKT\/Nrf2-NLRP3 pathway. Journal of Cellular and Molecular Medicine. 2021; 25: 9983\u20139994.","DOI":"10.1111\/jcmm.16871"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Wang YQ, Tang YF, Yang MK, Huang XZ. Dexmedetomidine alleviates cerebral ischemia-reperfusion injury in rats via inhibition of hypoxia-inducible factor-1\u03b1. Journal of Cellular Biochemistry. 2019; 120: 7834\u20137844.","DOI":"10.1002\/jcb.28058"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Zhang Q, Liu X, Hu Q, Liu Z, Liu Z, Zhang H, et al. Dexmedetomidine inhibits mitochondria damage and apoptosis of enteric glial cells in experimental intestinal ischemia\/reperfusion injury via SIRT3-dependent PINK1\/HDAC3\/p53 pathway. Journal of Translational Medicine. 2021; 19: 463.","DOI":"10.1186\/s12967-021-03027-6"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Gonullu E, Ozkardesler S, Kume T, Duru LS, Akan M, Guneli ME, et al. Comparison of the effects of dexmedetomidine administered at two different times on renal ischemiareperfusion injury in rats. Brazilian Journal of Anesthesiology. 2014; 64: 152\u2013158.","DOI":"10.1016\/j.bjane.2013.06.002"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Wang Y, Liu Z, Shu S, Cai J, Tang C, Dong Z. AMPK\/mTOR Signaling in Autophagy Regulation During Cisplatin-Induced Acute Kidney Injury. Frontiers in physiology. 2020; 11: 619730.","DOI":"10.3389\/fphys.2020.619730"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Yang T, Feng X, Zhao Y, Zhang H, Cui H, Wei M, et al. Dexmedetomidine Enhances Autophagy via \u03b12-AR\/AMPK\/mTOR Pathway to Inhibit the Activation of NLRP3 Inflammasome and Subsequently Alleviates Lipopolysaccharide-Induced Acute Kidney Injury. Frontiers in Pharmacology. 2020; 11: 790.","DOI":"10.3389\/fphar.2020.00790"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Kaushal GP, Shah SV. Autophagy in acute kidney injury. Kidney International. 2016; 89: 779\u2013791.","DOI":"10.1016\/j.kint.2015.11.021"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Liu DX, Zhang D, Hu WM, Chang YF, Wang XH, Li L. Geniposide protection against A\u03b21-42 toxicity correlates with mTOR inhibition and enhancement of autophagy. Journal of Integrative Neuroscience. 2021; 20: 67\u201375.","DOI":"10.31083\/j.jin.2021.01.242"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Tian L, Tang G, Liu Q, Yin Y, Li Y, Zhong Y. Blockade of adenosine a1 receptor in nucleus tractus solitarius attenuates baroreflex sensitivity response to dexmedetomidine in rats. Brain Research. 2020; 1743: 146949.","DOI":"10.1016\/j.brainres.2020.146949"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Bao J, Shi Y, Tao M, Liu N, Zhuang S, Yuan W. Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy. Clinical Science. 2018; 132: 2299\u20132322.","DOI":"10.1042\/CS20180563"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Ferr\u00e8 S, Deng Y, Huen SC, Lu CY, Scherer PE, Igarashi P, et al. Renal tubular cell spliced X-box binding protein 1 (Xbp1s) has a unique role in sepsis-induced acute kidney injury and inflammation. Kidney International. 2019; 96: 1359\u20131373.","DOI":"10.1016\/j.kint.2019.06.023"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Wu P, Su Y, Feng L, Jiang W, Kuang S, Tang L, et al. Optimal DL-Methionyl-DL-Methionine Supplementation Improved Intestinal Physical Barrier Function by Changing Antioxidant Capacity, Apoptosis and Tight Junction Proteins in the Intestine of Juvenile Grass Carp (Ctenopharyngodon idella). Antioxidants. 2022; 11: 1652.","DOI":"10.3390\/antiox11091652"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Qiu R, Yao W, Ji H, Yuan D, Gao X, Sha W, et al. Dexmedetomidine restores septic renal function via promoting inflammation resolution in a rat sepsis model. Life Sciences. 2018; 204: 1\u20138.","DOI":"10.1016\/j.lfs.2018.05.001"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Zhu H, Wang W, Li Y. Molecular Mechanism and Regulation of Autophagy and Its Potential Role in Epilepsy. Cells. 2022; 11: 2621.","DOI":"10.3390\/cells11172621"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Rezabakhsh A, Vahed N, Hosseinifard H, Rahbarghazi R, Salehnia F, Sadeghpour Y, et al. Dichotomous effects of autophagy on infarct volume in experimental permanent\/transient ischemic stroke model: a systematic review and meta-analysis. Journal of Integrative Neuroscience. 2022; 21: 11.","DOI":"10.31083\/j.jin2101011"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Li F, Song L, Yang X, Huang Z, Mou X, Syed A, et al. Anticancer and genotoxicity effect of (Clausena lansium (Lour.) Skeels) Peel ZnONPs on neuroblastoma (SH-SY5Y) cells through the modulation of autophagy mechanism. Journal of Photochemistry and Photobiology B: Biology. 2020; 203: 111748.","DOI":"10.1016\/j.jphotobiol.2019.111748"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nature Reviews Immunology. 2013; 13: 722\u2013737.","DOI":"10.1038\/nri3532"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Guo L, He N, Zhao Y, Liu T, Deng Y. Autophagy Modulated by Inorganic Nanomaterials. Theranostics. 2020; 10: 3206\u20133222.","DOI":"10.7150\/thno.40414"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Li T, Jiang S, Yang Z, Ma Z, Yi W, Wang D, et al. Targeting the energy guardian AMPK: another avenue for treating cardiomyopathy? Cellular and Molecular Life Sciences. 2017; 74: 1413\u20131429.","DOI":"10.1007\/s00018-016-2407-7"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Jiang S, Li T, Yang Z, Yi W, Di S, Sun Y, et al. AMPK orchestrates an elaborate cascade protecting tissue from fibrosis and aging. Ageing Research Reviews. 2017; 38: 18\u201327.","DOI":"10.1016\/j.arr.2017.07.001"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Hardie DG. The AMP-activated protein kinase pathway\u2013new players upstream and downstream. Journal of Cell Science. 2004; 117: 5479\u20135487.","DOI":"10.1242\/jcs.01540"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Ix JH, Sharma K. Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. Journal of the American Society of Nephrology. 2010; 21: 406\u2013412.","DOI":"10.1681\/ASN.2009080820"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"Alers S, L\u00f6ffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1\/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks. Molecular and Cellular Biology. 2012; 32: 2\u201311.","DOI":"10.1128\/MCB.06159-11"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Liu J, Livingston MJ, Dong G, Tang C, Su Y, Wu G, et al. Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells. Cell Death & Disease. 2018; 9: 322.","DOI":"10.1038\/s41419-018-0374-7"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"Pan JS, Huang L, Belousova T, Lu L, Yang Y, Reddel R, et al. Stanniocalcin-1 Inhibits Renal Ischemia\/Reperfusion Injury via an AMP-Activated Protein Kinase-Dependent Pathway. Journal of the American Society of Nephrology. 2015; 26: 364\u2013378.","DOI":"10.1681\/ASN.2013070703"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"Yadav RK, Lee G, Lee H, Li B, Jung H, Rashid H, et al. TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine a-induced nephrotoxicity model. Autophagy. 2015; 11: 1760\u20131774.","DOI":"10.1080\/15548627.2015.1082021"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"Fan K, Lin L, Ai Q, Wan J, Dai J, Liu G, et al. Lipopolysaccharide-Induced Dephosphorylation of AMPK-Activated Protein Kinase Potentiates Inflammatory Injury via Repression of ULK1-Dependent Autophagy. Frontiers in Immunology. 2018; 9: 1464.","DOI":"10.3389\/fimmu.2018.01464"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"Xi M, Zhao P, Li F, Bao H, Ding S, Ji L, et al. MicroRNA-16 inhibits the TLR4\/NF-\u03baB pathway and maintains tight junction integrity in irritable bowel syndrome with diarrhea. The Journal of biological chemistry. 2022; 298: 102461.","DOI":"10.1016\/j.jbc.2022.102461"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"Mann JP, Vito RD, Mosca A, Alisi A, Armstrong MJ, Raponi M, et al. Portal inflammation is independently associated with fibrosis and metabolic syndrome in pediatric nonalcoholic fatty liver disease. Hepatology. 2016; 63: 745\u2013753.","DOI":"10.1002\/hep.28374"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"Schaffer JM, Singh SK, Reitz BA, Zamanian RT, Mallidi HR. Single- vs Double-Lung Transplantation in Patients with Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis since the Implementation of Lung Allocation Based on Medical need. The Journal of American Medical Association. 2015; 313: 936\u2013948.","DOI":"10.1001\/jama.2015.1175"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"Fantus D, Rogers NM, Grahammer F, Huber TB, Thomson AW. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nature Reviews Nephrology. 2016; 12: 587\u2013609.","DOI":"10.1038\/nrneph.2016.108"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"Kim J, Kundu M, Viollet B, Guan K. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology. 2011; 13: 132\u2013141.","DOI":"10.1038\/ncb2152"},{"key":"ref42","doi-asserted-by":"crossref","unstructured":"Kim TW, Kim YJ, Kim HT, Park SR, Lee MY, Park YD, Lee CH, Jung JY. NQO1 Deficiency Leads Enhanced Autophagy in Cisplatin-Induced Acute Kidney Injury Through the AMPK\/TSC2\/mTOR Signaling Pathway. Antioxidants & Redox Signaling. 2016; 24: 867\u2013883.","DOI":"10.1089\/ars.2015.6386"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/28\/12\/10.31083\/j.fbl2812323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T13:02:52Z","timestamp":1732712572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/28\/12\/10.31083\/j.fbl2812323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,1]]},"references-count":42,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023]]}},"alternative-id":["S2768-6701(23)00946-2"],"URL":"https:\/\/doi.org\/10.31083\/j.fbl2812323","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,1]]},"article-number":"323"}}