{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T22:27:47Z","timestamp":1762900067191,"version":"build-2065373602"},"reference-count":65,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UIDB 50006\/2020"],"award-info":[{"award-number":["UIDB 50006\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a cI\u00eancia e Tecnologia","award":["PTDC\/SAU-FCF\/67764\/2006","SFRH\/BD\/43187\/2008"],"award-info":[{"award-number":["PTDC\/SAU-FCF\/67764\/2006","SFRH\/BD\/43187\/2008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Diabetic nephropathy (DN) and hypertension are prime causes for end-stage renal disease (ESRD) that often coexist in patients, but are seldom studied in combination. Kidney adenosine levels are markedly increased in diabetes, and the expression and function of renal adenosine receptors are altered in experimental diabetes. The aim of this work is to explore the impact of endogenous and exogenous adenosine on the expression\/distribution profile of its receptors along the nephron of hypertensive rats with experimentally-induced diabetes. Using spontaneously hypertensive (SHR) rats rendered diabetic with streptozotocin (STZ), we show that treatment of SHR-STZ rats with an agonist of adenosine receptors increases A2A immunoreactivity in superficial glomeruli (SG), proximal tubule (PCT), and distal tubule (DCT). Differently, treatment of SHR-STZ rats with a xanthinic antagonist of adenosine receptors decreases adenosine A3 immunoreactivity in SG, PCT, DCT, and collecting duct. There is no difference in the immunoreactivity against the adenosine A1 and A2B receptors between the experimental groups. The agonist of adenosine receptors ameliorates renal fibrosis, probably via A2A receptors, while the antagonist exacerbates it, most likely due to tonic activation of A3 receptors. The reduction in adenosine A3 immunoreactivity might be due to receptor downregulation in response to prolonged activation. Altogether, these results suggest an opposite regulation exerted by endogenous and exogenous adenosine upon the expression of its A2A and A3 receptors along the nephron of hypertensive diabetic rats, which has a functional impact and should be taken into account when considering novel therapeutic targets for hypertensive-diabetic nephropathy.<\/jats:p>","DOI":"10.3390\/biomedicines8110529","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T08:18:23Z","timestamp":1606119503000},"page":"529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Adenosine A2A and A3 Receptors as Targets for the Treatment of Hypertensive-Diabetic Nephropathy"],"prefix":"10.3390","volume":"8","author":[{"given":"Daniela","family":"Patinha","sequence":"first","affiliation":[{"name":"Department of Biomedicine\u2014Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal"},{"name":"The Institute of Biomedical and Clinical Science, Medical School, University of Exeter, EX4 4QJ Exeter, UK"}]},{"given":"Carla","family":"Abreu","sequence":"additional","affiliation":[{"name":"LAQV@REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Carla","family":"Carvalho","sequence":"additional","affiliation":[{"name":"LAQV@REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Olga Mariana","family":"Cunha","sequence":"additional","affiliation":[{"name":"LAQV@REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Mariana","family":"Mota","sequence":"additional","affiliation":[{"name":"LAQV@REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Joana","family":"Afonso","sequence":"additional","affiliation":[{"name":"Department of Biomedicine\u2014Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal"},{"name":"MedInUP\u2014Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7230-5020","authenticated-orcid":false,"given":"Teresa","family":"Sousa","sequence":"additional","affiliation":[{"name":"Department of Biomedicine\u2014Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal"},{"name":"MedInUP\u2014Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Ant\u00f3nio","family":"Albino-Teixeira","sequence":"additional","affiliation":[{"name":"Department of Biomedicine\u2014Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal"},{"name":"MedInUP\u2014Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4668-9360","authenticated-orcid":false,"given":"Carmen","family":"Diniz","sequence":"additional","affiliation":[{"name":"LAQV@REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9509-0613","authenticated-orcid":false,"given":"Manuela","family":"Morato","sequence":"additional","affiliation":[{"name":"LAQV@REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.mam.2017.01.004","article-title":"Adenosine contribution to normal renal physiology and chronic kidney disease","volume":"55","author":"Oyarzun","year":"2017","journal-title":"Mol. Aspects Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/ki.1989.126","article-title":"Adenosine induces mesangial cell contraction by an a1-type receptor","volume":"35","author":"Olivera","year":"1989","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1681\/ASN.2007060721","article-title":"Lack of a1 adenosine receptors augments diabetic hyperfiltration and glomerular injury","volume":"19","author":"Chen","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1016\/j.ajpath.2016.06.017","article-title":"Macrophage a2a adenosine receptors are essential to protect from progressive kidney injury","volume":"186","author":"Truong","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.3346\/jkms.2016.31.9.1403","article-title":"Renoprotective effects of a highly selective a3 adenosine receptor antagonist in a mouse model of adriamycin-induced nephropathy","volume":"31","author":"Min","year":"2016","journal-title":"J. Korean Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1681\/ASN.2007030276","article-title":"Activation of adenosine 2a receptors preserves structure and function of podocytes","volume":"19","author":"Awad","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1096\/fj.07-8213com","article-title":"Adenosine receptor activation ameliorates type 1 diabetes","volume":"21","author":"Nemeth","year":"2007","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1161\/01.HYP.0000178464.63393.88","article-title":"Adenosine inhibits pdgf-induced growth of human glomerular mesangial cells via a(2b) receptors","volume":"46","author":"Dubey","year":"2005","journal-title":"Hypertension"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.bbrc.2007.11.113","article-title":"Adenosine a(2b) receptor mediates an increase on vegf-a production in rat kidney glomeruli","volume":"366","author":"Valladares","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","first-page":"339","article-title":"Adenosine signaling increases proinflammatory and profibrotic mediators through activation of a functional adenosine 2b receptor in renal fibroblasts","volume":"46","author":"Wilkinson","year":"2016","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1046\/j.1523-1755.2002.00256.x","article-title":"Adenosine-induced apoptosis in glomerular mesangial cells","volume":"61","author":"Zhao","year":"2002","journal-title":"Kidney Int."},{"key":"ref_12","first-page":"28","article-title":"Diabetes and end-stage renal disease; a review article on new concepts","volume":"4","author":"Ghaderian","year":"2015","journal-title":"J. Renal Inj. Prev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.3390\/ijms21082806","article-title":"Macrophage phenotype and fibrosis in diabetic nephropathy","volume":"21","author":"Calle","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"269","DOI":"10.4239\/wjd.v10.i5.269","article-title":"Evolving spectrum of diabetic nephropathy","volume":"10","author":"Kopel","year":"2019","journal-title":"World J. Diabetes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1161\/HYPERTENSIONAHA.117.10546","article-title":"Hypertension and diabetes mellitus: Coprediction and time trajectories","volume":"71","author":"Tsimihodimos","year":"2018","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/S0140-6736(13)60687-X","article-title":"Chronic kidney disease: Global dimension and perspectives","volume":"382","author":"Jha","year":"2013","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s00125-009-1268-0","article-title":"Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis","volume":"52","author":"Magee","year":"2009","journal-title":"Diabetologia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1016\/j.febslet.2009.09.003","article-title":"Adenosine mediates transforming growth factor-beta 1 release in kidney glomeruli of diabetic rats","volume":"583","author":"Roa","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"490","DOI":"10.2174\/1389450111314040010","article-title":"Targeting adenosine signaling to treatment of diabetic nephropathy","volume":"14","author":"Quezada","year":"2013","journal-title":"Curr. Drug Targets"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3109\/03009734.2013.851748","article-title":"Activation of adenosine receptors improves renal antioxidant status in diabetic wistar but not shr rats","volume":"119","author":"Patinha","year":"2014","journal-title":"Ups. J. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"F614","DOI":"10.1152\/ajprenal.00285.2012","article-title":"Angiotensin ii contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type i receptors","volume":"304","author":"Patinha","year":"2013","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0002-9440(10)62977-X","article-title":"Region-specific alterations of adenosine receptors expression level in kidney of diabetic rat","volume":"167","author":"Pawelczyk","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2174\/1871528111312030001","article-title":"Adenosine receptors: New therapeutic targets for inflammation in diabetic nephropathy","volume":"12","author":"Elsherbiny","year":"2013","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"F828","DOI":"10.1152\/ajprenal.00310.2005","article-title":"Adenosine a2a receptor activation attenuates inflammation and injury in diabetic nephropathy","volume":"290","author":"Awad","year":"2006","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/ki.2014.244","article-title":"The role of adenosine receptors a2a and a2b signaling in renal fibrosis","volume":"86","author":"Roberts","year":"2014","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0006-2952(00)00532-3","article-title":"Immunolocalisation of adenosine a(1) receptors in the rat kidney","volume":"61","author":"Smith","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","first-page":"F991","article-title":"Adenosine receptor gene expression in rat kidney","volume":"263","author":"Weaver","year":"1992","journal-title":"Am. J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1111\/j.1523-1755.2004.00490.x","article-title":"Gene expression of adenosine receptors along the nephron","volume":"65","author":"Vitzthum","year":"2004","journal-title":"Kidney Int."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Patinha, D., Carvalho, C., Abreu, C., Cunha, O.M., Mota, M.C., Afonso, J., Albino-Teixeira, A., Diniz, C., and Morato, M. (2019). Diabetes downregulates renal adenosine a2a receptors in an experimental model of hypertension. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0217552"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/0976-500X.72351","article-title":"Improving bioscience research reporting: The arrive guidelines for reporting animal research","volume":"1","author":"Kilkenny","year":"2010","journal-title":"J. Pharmacol. Pharmacother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1159\/000139033","article-title":"Structure-activity relationships for 2-substituted adenosines at a1 and a2 adenosine receptors","volume":"46","author":"Daly","year":"1993","journal-title":"Pharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1021\/jm00382a018","article-title":"1,3-dialkyl-8-(p-sulfophenyl)xanthines: Potent water-soluble antagonists for a1- and a2-adenosine receptors","volume":"28","author":"Daly","year":"1985","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1093\/ndt\/gfq150","article-title":"Glycaemic control with insulin prevents the reduced renal dopamine d1 receptor expression and function in streptozotocin-induced diabetes","volume":"25","author":"Serrao","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1002\/jemt.20609","article-title":"Immunohistochemical characterization of adenosine receptors in rat aorta and tail arteries","volume":"71","author":"Leal","year":"2008","journal-title":"Microsc. Res. Technol."},{"key":"ref_35","first-page":"407","article-title":"Vascular impairment of adenosinergic system in hypertension: Increased adenosine bioavailability and differential distribution of adenosine receptors and nucleoside transporters","volume":"51","author":"Brandao","year":"2019","journal-title":"Histochem. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.lfs.2009.03.006","article-title":"A1 receptors mediate adenosine inhibitory effects in mouse ileum via activation of potassium channels","volume":"84","author":"Zizzo","year":"2009","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"40104","DOI":"10.1074\/jbc.M110.184606","article-title":"Inactivation of adenosine a2a receptor attenuates basal and angiotensin ii-induced ros production by nox2 in endothelial cells","volume":"285","author":"Thakur","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1182\/blood-2007-10-117044","article-title":"A2b adenosine receptor dampens hypoxia-induced vascular leak","volume":"111","author":"Eckle","year":"2008","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1677\/joe.1.06714","article-title":"Adenosine does not bind to the growth hormone secretagogue receptor type-1a (ghs-r1a)","volume":"191","author":"Carreira","year":"2006","journal-title":"J. Endocrinol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ab.2006.07.017","article-title":"Semiautomated computer-assisted image analysis to quantify 3,3\u2019-diaminobenzidine tetrahydrochloride-immunostained small tissues","volume":"357","author":"Leal","year":"2006","journal-title":"Anal. Biochem."},{"key":"ref_41","first-page":"1516","article-title":"Microscopic image analysis using computer-assisted methodology to Quantify immunostained receptors","volume":"Volume 2","year":"2010","journal-title":"Microscopy: Science, Technology, Applications and Education"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e00669","DOI":"10.1016\/j.heliyon.2018.e00669","article-title":"Automated analysis of images for molecular quantification in immunohistochemistry","volume":"4","author":"Guirado","year":"2018","journal-title":"Heliyon"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00418-018-1635-3","article-title":"Histomorphometric analyses of human adipose tissues using intact, flash-frozen samples","volume":"149","author":"Laforest","year":"2018","journal-title":"Histochem. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cmpb.2017.12.014","article-title":"Immunohistochemical quantification of expression of a tight junction protein, claudin-7, in human lung cancer samples using digital image analysis method","volume":"155","author":"Lu","year":"2018","journal-title":"Comput. Methods Programs. Biomed."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ejphar.2008.04.044","article-title":"Role of superoxide and hydrogen peroxide in hypertension induced by an antagonist of adenosine receptors","volume":"588","author":"Sousa","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.lfs.2014.05.011","article-title":"Diabetes-induced increase of renal medullary hydrogen peroxide and urinary angiotensinogen is similar in normotensive and hypertensive rats","volume":"108","author":"Patinha","year":"2014","journal-title":"Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1681\/ASN.2009091005","article-title":"Morphometric and visual evaluation of fibrosis in renal biopsies","volume":"22","author":"Farris","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/ki.2011.101","article-title":"Adenosine a(2a) receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation","volume":"80","author":"Garcia","year":"2011","journal-title":"Kidney Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/S0005-2736(97)00121-1","article-title":"Effect of adenosine on the ouabain-insensitive na+-atpase activity from basolateral membrane of the proximal tubule","volume":"1329","author":"Souza","year":"1997","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Vallon, V., and Osswald, H. (2009). Adenosine receptors and the kidney. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/978-3-540-89615-9_15"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"F1141","DOI":"10.1152\/ajprenal.2001.281.6.F1141","article-title":"Adenosine modulates mg(2+) uptake in distal convoluted tubule cells via a(1) and a(2) purinoceptors","volume":"281","author":"Kang","year":"2001","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/hdi.12159","article-title":"Hypomagnesemia, chronic kidney disease and cardiovascular mortality: Pronounced association but unproven causation","volume":"18","author":"Dousdampanis","year":"2014","journal-title":"Hemodial. Int."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Muller, C.E., and Jacobson, K.A. (2011). Xanthines as adenosine receptor antagonists. Handbook of Experimental Pharmacology, Springer.","DOI":"10.1007\/978-3-642-13443-2_6"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1007\/s12272-018-1079-2","article-title":"Correlation study between a3 adenosine receptor binding affinity and anti-renal interstitial fibrosis activity of truncated adenosine derivatives","volume":"42","author":"Yu","year":"2019","journal-title":"Arch. Pharm. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4531","DOI":"10.3390\/ijms20184531","article-title":"Blockade of the adenosine a3 receptor attenuates caspase 1 activation in renal tubule epithelial cells and decreases interleukins il-1beta and il-18 in diabetic rats","volume":"20","author":"Garrido","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Borea, P.A. (2010). The desensitisation as a3 adenosine receptor regulation: Physiopathological implications. A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics, Springer.","DOI":"10.1007\/978-90-481-3144-0"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"785","DOI":"10.3390\/cells9030785","article-title":"Focusing on adenosine receptors as a potential targeted therapy in human diseases","volume":"9","author":"Effendi","year":"2020","journal-title":"Cells"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/med.21456","article-title":"A3 adenosine receptors as modulators of inflammation: From medicinal chemistry to therapy","volume":"38","author":"Jacobson","year":"2018","journal-title":"Med. Res. Rev."},{"key":"ref_59","first-page":"752","article-title":"Diuretic response to adenosine a(1) receptor blockade in normotensive and spontaneously hypertensive rats: Role of pertussis toxin-sensitive g-proteins","volume":"292","author":"Kost","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/labinvest.2012.143","article-title":"Adenosine a(2b) receptor-mediated vegf induction promotes diabetic glomerulopathy","volume":"93","author":"Cardenas","year":"2013","journal-title":"Lab. Invest."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11302-007-9086-7","article-title":"Internalization and desensitization of adenosine receptors","volume":"4","author":"Klaasse","year":"2008","journal-title":"Purinergic. Signal."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.bbamem.2010.06.007","article-title":"Adenosine receptor desensitization and trafficking","volume":"1808","author":"Mundell","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17610","DOI":"10.1074\/jbc.273.28.17610","article-title":"Adenosine deaminase and a1 adenosine receptors internalize together following agonist-induced receptor desensitization","volume":"273","author":"Saura","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2005.08.052","article-title":"Allosteric modulators affect the internalization of human adenosine a1 receptors","volume":"522","author":"Klaasse","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1124\/mol.57.3.546","article-title":"Subtype-specific kinetics of inhibitory adenosine receptor internalization are determined by sensitivity to phosphorylation by g protein-coupled receptor kinases","volume":"57","author":"Ferguson","year":"2000","journal-title":"Mol. Pharmacol."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/8\/11\/529\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:35:51Z","timestamp":1760178951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/8\/11\/529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,23]]},"references-count":65,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["biomedicines8110529"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines8110529","relation":{},"ISSN":["2227-9059"],"issn-type":[{"type":"electronic","value":"2227-9059"}],"subject":[],"published":{"date-parts":[[2020,11,23]]}}}