{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T05:30:32Z","timestamp":1772861432201,"version":"3.50.1"},"reference-count":56,"publisher":"Portland Press Ltd.","issue":"20","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,10,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to \u03b11 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wildtype mice were treated with prazosin 12 h after CLP or nitric oxide synthase 2 (NOS-2) inhibitor, 30 min before and 6 and 12 h after CLP. In vivo experiments and biochemistry assays were performed 24 h after CLP. Sepsis decreased the systemic mean arterial pressure (MAP) and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decrease in GRK2 level associated with an increase in \u03b11 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400 W. Treatment of non-septic mice with an NO donor reduced GRK2 content in the kidney. Therefore, our results show that an NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal \u03b11 adrenergic receptor density. The preservation of the density and\/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.<\/jats:p>","DOI":"10.1042\/cs20210462","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T09:54:17Z","timestamp":1633686857000},"page":"2341-2356","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dynamics of GRK2 in the kidney: a putative mechanism for sepsis-associated kidney injury"],"prefix":"10.1042","volume":"135","author":[{"given":"Thiele\u00a0Osvaldt","family":"Rosales","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f4nica\u00a0Vargas","family":"Horewicz","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Universidade do Sul de Santa Catarina, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcella\u00a0Amorim","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geisson\u00a0Marcos","family":"Nardi","sequence":"additional","affiliation":[{"name":"Department of Morphological Sciences, Universidade Federal de Santa Catarina, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8582-1569","authenticated-orcid":false,"given":"Jamil","family":"Assreuy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"key":"2021113011240406100_B1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"2021113011240406100_B2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.4161\/viru.27372","article-title":"Epidemiology of severe sepsis","volume":"5","author":"Mayr","year":"2014","journal-title":"Virulence"},{"key":"2021113011240406100_B3","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1001\/jama.2016.0289","article-title":"Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Shankar-Hari","year":"2016","journal-title":"JAMA"},{"key":"2021113011240406100_B4","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1097\/00003246-200107000-00002","article-title":"Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care","volume":"29","author":"Angus","year":"2001","journal-title":"Crit. Care Med."},{"key":"2021113011240406100_B5","doi-asserted-by":"publisher","first-page":"425","DOI":"10.2165\/00019053-200826050-00006","article-title":"A multicentre, prospective study to evaluate costs of septic patients in Brazilian intensive care units","volume":"26","author":"Sogayar","year":"2008","journal-title":"Pharmacoeconomics"},{"key":"2021113011240406100_B6","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1097\/01.CCM.0000117317.18092.E4","article-title":"Surviving sepsis campaign guidelines for management of severe sepsis and septic shock","volume":"32","author":"Dellinger","year":"2004","journal-title":"Crit. Care Med."},{"key":"2021113011240406100_B7","doi-asserted-by":"publisher","first-page":"i1585","DOI":"10.1136\/bmj.i1585","article-title":"Sepsis: pathophysiology and clinical management","volume":"353","author":"Gotts","year":"2016","journal-title":"BMJ"},{"key":"2021113011240406100_B8","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s40779-016-0099-9","article-title":"Pathophysiology of sepsis-induced myocardial dysfunction","volume":"3","author":"Lv","year":"2016","journal-title":"Mil. Med. Res."},{"key":"2021113011240406100_B9","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.ccc.2017.08.005","article-title":"Pathophysiology of septic shock","volume":"34","author":"Russell","year":"2018","journal-title":"Crit. Care Clin."},{"key":"2021113011240406100_B10","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/j.mito.2004.07.023","article-title":"Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome","volume":"4","author":"Crouser","year":"2004","journal-title":"Mitochondrion"},{"key":"2021113011240406100_B11","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.ijid.2008.05.1231","article-title":"Acute kidney injury in patients with sepsis: a contemporary analysis","volume":"13","author":"Lopes","year":"2009","journal-title":"Int. J. Infect. Dis."},{"key":"2021113011240406100_B12","doi-asserted-by":"publisher","first-page":"k4891","DOI":"10.1136\/bmj.k4891","article-title":"Sepsis associated acute kidney injury","volume":"364","author":"Poston","year":"2019","journal-title":"BMJ"},{"key":"2021113011240406100_B13","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/j.kint.2019.05.026","article-title":"Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment","volume":"96","author":"Peerapornratana","year":"2019","journal-title":"Kidney Int."},{"key":"2021113011240406100_B14","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1097\/MCC.0000000000000153","article-title":"Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies","volume":"20","author":"Zarbock","year":"2014","journal-title":"Curr. Opin. Crit. Care"},{"key":"2021113011240406100_B15","doi-asserted-by":"publisher","first-page":"e12483","DOI":"10.1111\/micc.12483","article-title":"Sepsis-induced acute kidney injury: a disease of the microcirculation","volume":"26","author":"Ma","year":"2018","journal-title":"Microcirculation"},{"key":"2021113011240406100_B16","doi-asserted-by":"publisher","first-page":"2178","DOI":"10.1093\/ndt\/gfu052","article-title":"Glomerular haemodynamics, the renal sympathetic nervous system and sepsis-induced acute kidney injury","volume":"29","author":"Calzavacca","year":"2014","journal-title":"Nephrol. Dial. Transplant."},{"key":"2021113011240406100_B17","doi-asserted-by":"publisher","first-page":"H1065","DOI":"10.1152\/ajpheart.01237.2006","article-title":"Impairments in microvascular reactivity are related to organ failure in human sepsis","volume":"293","author":"Doerschug","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021113011240406100_B18","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1093\/bjaceaccp\/mkv003","article-title":"Pathophysiology of cardiovascular dysfunction in sepsis","volume":"15","author":"Greer","year":"2015","journal-title":"BJA Educ."},{"key":"2021113011240406100_B19","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1097\/01.CCM.0000218812.73741.6C","article-title":"Effects of vasopressin, norepinephrine, and L-arginine on intestinal microcirculation in endotoxemia","volume":"34","author":"Nakajima","year":"2006","journal-title":"Crit. Care Med."},{"key":"2021113011240406100_B20","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1681\/ASN.2004060441","article-title":"Maintenance of renal vascular reactivity contributes to acute renal failure during endotoxemic shock","volume":"16","author":"Boffa","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113011240406100_B21","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S0272-6386(12)80692-5","article-title":"Sepsis-associated renal vasoconstriction: potential targets for future therapy","volume":"20","author":"Badr","year":"1992","journal-title":"Am. J. Kidney Dis."},{"key":"2021113011240406100_B22","first-page":"959","article-title":"Regional differences in the effects of septic shock on vascular reactivity in the rabbit","volume":"261","author":"Li","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021113011240406100_B23","doi-asserted-by":"publisher","first-page":"165","DOI":"10.2174\/187153006777442314","article-title":"Nitric oxide and cardiovascular dysfunction in sepsis","volume":"6","author":"Assreuy","year":"2006","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"2021113011240406100_B24","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.lfs.2003.10.042","article-title":"iNOS-mediated nitric oxide production and its regulation","volume":"75","author":"Aktan","year":"2004","journal-title":"Life Sci."},{"key":"2021113011240406100_B25","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1097\/00003246-199804000-00012","article-title":"Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study","volume":"26","author":"Avontuur","year":"1998","journal-title":"Crit. Care Med."},{"key":"2021113011240406100_B26","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/S0014-2999(00)00660-9","article-title":"Cardiac and vascular effects of nitric oxide synthase inhibition in lipopolysaccharide-treated rats","volume":"406","author":"Shan","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"2021113011240406100_B27","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1124\/mol.105.015479","article-title":"Nitric oxide-dependent reduction in soluble guanylate cyclase functionality accounts for early lipopolysaccharide-induced changes in vascular reactivity","volume":"69","author":"Fernandes","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"2021113011240406100_B28","doi-asserted-by":"publisher","first-page":"H149","DOI":"10.1152\/ajpheart.00052.2016","article-title":"Cardiac hyporesponsiveness in severe sepsis is associated with nitric oxide-dependent activation of G protein receptor kinase","volume":"313","author":"Dal-Secco","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021113011240406100_B29","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1097\/SHK.0b013e3181994752","article-title":"Inhibition of NF-kappaB activity prevents downregulation of alpha1-adrenergic receptors and circulatory failure during CLP-induced sepsis","volume":"32","author":"Schmidt","year":"2009","journal-title":"Shock"},{"key":"2021113011240406100_B30","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/S1499-3872(13)60047-8","article-title":"Desensitization of G-protein-coupled receptors induces vascular hypocontractility in response to norepinephrine in the mesenteric arteries of cirrhotic patients and rats","volume":"12","author":"Chen","year":"2013","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"2021113011240406100_B31","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1096\/fasebj.9.2.7781920","article-title":"Protein kinases that phosphorylate activated G protein-coupled receptors","volume":"9","author":"Premont","year":"1995","journal-title":"FASEB J."},{"key":"2021113011240406100_B32","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/S0022-2828(86)80003-7","article-title":"Regulation of adrenergic receptor function by phosphorylation","volume":"18","author":"Lefkowitz","year":"1986","journal-title":"J. Mol. Cell Cardiol."},{"key":"2021113011240406100_B33","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.cellsig.2017.07.004","article-title":"G protein-coupled receptor kinases: past, present and future","volume":"41","author":"Komolov","year":"2018","journal-title":"Cell. Signal."},{"key":"2021113011240406100_B34","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.cardiores.2005.09.011","article-title":"Mechanisms of regulation of G protein-coupled receptor kinases (GRKs) and cardiovascular disease","volume":"69","author":"Penela","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"2021113011240406100_B35","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3389\/fphar.2019.00112","article-title":"Protein-coupled receptor kinase 2 (GRK2) as a potential therapeutic target in cardiovascular and metabolic diseases","volume":"10","author":"Murga","year":"2019","journal-title":"Front. Pharmacol."},{"key":"2021113011240406100_B36","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nprot.2008.214","article-title":"Immunodesign of experimental sepsis by cecal ligation and puncture","volume":"4","author":"Rittirsch","year":"2009","journal-title":"Nat. Protoc."},{"key":"2021113011240406100_B37","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/S0076-6879(96)68016-1","article-title":"Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction","volume":"268","author":"Granger","year":"1996","journal-title":"Methods Enzymol."},{"key":"2021113011240406100_B38","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2021113011240406100_B39","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1097\/00000658-197307000-00020","article-title":"Plasma catecholamines in patients with serious postoperative infection","volume":"178","author":"Groves","year":"1973","journal-title":"Ann. Surg."},{"key":"2021113011240406100_B40","first-page":"715","article-title":"Plasma catecholamine levels and pulmonary dysfunction in sepsis","volume":"148","author":"Bocking","year":"1979","journal-title":"Surg. Gynecol. Obstet."},{"key":"2021113011240406100_B41","doi-asserted-by":"publisher","first-page":"R328","DOI":"10.1186\/cc2902","article-title":"Erythropoietin and renin as biological markers in critically ill patients","volume":"8","author":"Tamion","year":"2004","journal-title":"Crit. Care"},{"key":"2021113011240406100_B42","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1177\/1074248415587968","article-title":"Erythropoietin reverses sepsis-induced vasoplegia to norepinephrine through preservation of \u03b11D-adrenoceptor mRNA expression and inhibition of GRK2-mediated desensitization in mouse aorta","volume":"21","author":"Kandasamy","year":"2016","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"2021113011240406100_B43","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1097\/FJC.0b013e3181e74d6a","article-title":"Differential involvement of potassium channel subtypes in early and late sepsis-induced hyporesponsiveness to vasoconstrictors","volume":"56","author":"Sordi","year":"2010","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"2021113011240406100_B44","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.redox.2016.09.016","article-title":"Impaired vascular function in sepsis-surviving rats mediated by oxidative stress and Rho-Kinase pathway","volume":"10","author":"de Souza","year":"2016","journal-title":"Redox Biol."},{"key":"2021113011240406100_B45","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1016\/j.jacc.2003.06.002","article-title":"Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress","volume":"42","author":"Pleiner","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021113011240406100_B46","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1124\/jpet.104.079541","article-title":"Heterodimerization with beta2-adrenergic receptors promotes surface expression and functional activity of alpha1D-adrenergic receptors","volume":"313","author":"Uberti","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021113011240406100_B47","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/978-1-4939-7526-6_16","article-title":"An ovine model for studying the pathophysiology of septic acute kidney injury","volume":"1717","author":"Lankadeva","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"2021113011240406100_B48","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s40560-016-0146-3","article-title":"Role of kidney injury in sepsis","volume":"4","author":"Doi","year":"2016","journal-title":"J. Intensive Care"},{"key":"2021113011240406100_B49","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1007\/s001340050768","article-title":"Beta-adrenergic receptor-dependent and -independent stimulation of adenylate cyclase is impaired during severe sepsis in humans","volume":"24","author":"Bernardin","year":"1998","journal-title":"Intensive Care Med."},{"key":"2021113011240406100_B50","first-page":"407","article-title":"Renal alpha 1-adrenergic receptor subtypes: MDCK-D1 cells, but not rat cortical membranes possess a single population of receptors","volume":"39","author":"Klijn","year":"1991","journal-title":"Mol. Pharmacol."},{"key":"2021113011240406100_B51","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1038\/ki.1997.213","article-title":"Distribution of alpha 1B-adrenergic receptor mRNA expression along rat nephron segments","volume":"51","author":"Umemura","year":"1997","journal-title":"Kidney Int."},{"key":"2021113011240406100_B52","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1161\/01.HYP.33.1.524","article-title":"Alpha1- and alpha2-adrenoceptor control of sodium transport reverses in developing hypertension","volume":"33","author":"Gesek","year":"1999","journal-title":"Hypertension"},{"key":"2021113011240406100_B53","doi-asserted-by":"publisher","first-page":"521","DOI":"10.3390\/ijms22020521","article-title":"Nitric oxide and S-nitrosylation in cardiac regulation: G protein-coupled receptor kinase-2 and \u03b2-arrestins as targets","volume":"22","author":"Kayki-Mutlu","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2021113011240406100_B54","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1097\/SHK.0b013e3181e37ea8","article-title":"Inhibition of guanylyl cyclase restores neutrophil migration and maintains bactericidal activity increasing survival in sepsis","volume":"35","author":"Paula-Neto","year":"2011","journal-title":"Shock"},{"key":"2021113011240406100_B55","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.cell.2007.02.046","article-title":"Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2","volume":"129","author":"Whalen","year":"2007","journal-title":"Cell"},{"key":"2021113011240406100_B56","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1124\/mol.104.008417","article-title":"\u00df-arrestin-dependent spontaneous \u03b11a-adrenoceptor endocytosis causes intracellular transportation of \u03b1-blockers via recycling compartments","volume":"67","author":"Pediani","year":"2005","journal-title":"Mol. Pharmacol."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/135\/20\/2341\/922077\/cs-2021-0462.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/135\/20\/2341\/922077\/cs-2021-0462.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:19:35Z","timestamp":1638274775000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/135\/20\/2341\/229891\/Dynamics-of-GRK2-in-the-kidney-a-putative"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10]]},"references-count":56,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2021,10,29]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20210462","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,10]]},"published":{"date-parts":[[2021,10]]}}}