{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:02:59Z","timestamp":1785769379637,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Orexin-A is a neuropeptide product of the lateral hypothalamus that acts on two receptors, OX1R and OX2R. The orexinergic system is involved in feeding, sleep, and pressure regulation. Recently, orexin-A levels have been found to be negatively correlated with renal function. Here, we analyzed orexin-A levels as well as the incidence of SNPs in the hypocretin neuropeptide precursor (HCRT) and its receptors, HCRTR1 and HCRTR2, in 64 patients affected by autosomal dominant polycystic kidney disease (ADPKD) bearing truncating mutations in the PKD1 or PKD2 genes. Twenty-four healthy volunteers constituted the control group. Serum orexin-A was assessed by ELISA, while the SNPs were investigated through Sanger sequencing. Correlations with the main clinical features of PKD patients were assessed. PKD patients showed impaired renal function (mean eGFR 67.8 \u00b1 34.53) and a statistically higher systolic blood pressure compared with the control group (p &lt; 0.001). Additionally, orexin-A levels in PKD patients were statistically higher than those in healthy controls (477.07 \u00b1 69.42 pg\/mL vs. 321.49 \u00b1 78.01 pg\/mL; p &lt; 0.001). Furthermore, orexin-A inversely correlated with blood pressure (p = 0.0085), while a direct correlation with eGFR in PKD patients was found. None of the analyzed SNPs showed any association with orexin-A levels in PKD. In conclusion, our data highlights the emerging role of orexin-A in renal physiology and its potential relevance to PKD. Further research is essential to elucidate the intricate mechanisms underlying orexin-A signaling in renal function and its therapeutic implications for PKD and associated cardiovascular complications.<\/jats:p>","DOI":"10.3390\/ijms25116243","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T11:50:09Z","timestamp":1717588209000},"page":"6243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased Expression of Orexin-A in Patients Affected by Polycystic Kidney Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Ersilia","family":"Nigro","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Ambientali, Biologiche, Farmaceutiche, Universit\u00e0 della Campania \u201cLuigi Vanvitelli\u201d, Via Vivaldi 43, 81100 Caserta, Italy"},{"name":"CEINGE-Biotecnologie Avanzate Scarl \u201cFranco Salvatore\u201d, Via G. Salvatore 486, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"D\u2019Arco","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Scarl \u201cFranco Salvatore\u201d, Via G. Salvatore 486, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1274-0332","authenticated-orcid":false,"given":"Fiorenzo","family":"Moscatelli","sequence":"additional","affiliation":[{"name":"Department of Human Sciences, Telematic University Pegaso, 80100 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pisani","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Nefrologia, Dipartimento di Sanit\u00e0 Pubblica, Universit\u00e0 di Napoli \u201cFederico II\u201d, Via Pansini 5, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5082-9499","authenticated-orcid":false,"given":"Maria","family":"Amicone","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Nefrologia, Dipartimento di Sanit\u00e0 Pubblica, Universit\u00e0 di Napoli \u201cFederico II\u201d, Via Pansini 5, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Riccio","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Nefrologia, Dipartimento di Sanit\u00e0 Pubblica, Universit\u00e0 di Napoli \u201cFederico II\u201d, Via Pansini 5, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Capuano","sequence":"additional","affiliation":[{"name":"Unit\u00e0 di Nefrologia, Dipartimento di Sanit\u00e0 Pubblica, Universit\u00e0 di Napoli \u201cFederico II\u201d, Via Pansini 5, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Argentino","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Scarl \u201cFranco Salvatore\u201d, Via G. Salvatore 486, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7184-218X","authenticated-orcid":false,"given":"Marcellino","family":"Monda","sequence":"additional","affiliation":[{"name":"Sezione di Fisiologia Umana e Unit\u00e0 di Dietetica e Medicina dello Sport, Dipartimento di Medicina Sperimentale, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Messina","sequence":"additional","affiliation":[{"name":"Sezione di Fisiologia Umana e Unit\u00e0 di Dietetica e Medicina dello Sport, Dipartimento di Medicina Sperimentale, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Daniele","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Scarl \u201cFranco Salvatore\u201d, Via G. Salvatore 486, 80145 Napoli, Italy"},{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi \u201cFederico II\u201d, Via Pansini 5, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Polito","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"278","DOI":"10.7861\/clinmedicine.9-3-278","article-title":"Autosomal dominant polycystic kidney disease","volume":"9","author":"Chow","year":"2009","journal-title":"Clin. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1681\/ASN.2012070650","article-title":"Type of PKD1 mutation influences renal outcome in ADPKD","volume":"24","author":"Chen","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrneph.2009.13","article-title":"Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease","volume":"5","author":"Ecder","year":"2009","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nigro, E., Amicone, M., D\u2019Arco, D., Sellitti, G., De Marco, O., Guarino, M., Riccio, E., Pisani, A., and Daniele, A. (2023). Molecular Diagnosis and Identification of Novel Pathogenic Variants in a Large Cohort of Italian Patients Affected by Polycystic Kidney Diseases. Genes, 14.","DOI":"10.3390\/genes14061236"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3389\/fped.2017.00279","article-title":"The Genetic and Cellular Basis of Autosomal Dominant Polycystic Kidney Disease-A Primer for Clinicians","volume":"5","author":"Cordido","year":"2017","journal-title":"Front. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3389\/fgene.2019.00044","article-title":"GANAB and PKD1 Variations in a 12 Years Old Female Patient with Early Onset of Autosomal Dominant Polycystic Kidney Disease","volume":"10","author":"Waldrop","year":"2019","journal-title":"Front. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/S0140-6736(07)60601-1","article-title":"Autosomal dominant polycystic kidney disease","volume":"369","author":"Torres","year":"2007","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pisani, A., Daniele, A., Di Domenico, C., Nigro, E., Salvatore, F., and Riccio, E. (2015). Late diagnosis of Fabry disease caused by a de novo mutation in a patient with end stage renal disease. BMC Res. Notes, 8.","DOI":"10.1186\/s13104-015-1696-5"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1053\/j.ackd.2009.12.004","article-title":"Determinants of renal disease variability in ADPKD","volume":"17","author":"Harris","year":"2010","journal-title":"Adv. Chronic Kidney Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1053\/j.ackd.2010.01.001","article-title":"Hypertension in autosomal dominant polycystic kidney disease","volume":"17","author":"Chapman","year":"2010","journal-title":"Adv. Chronic Kidney Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1161\/HYPERTENSIONAHA.122.19796","article-title":"Orexin, Sleep, Sympathetic Neural Activity, and Cardiovascular Function","volume":"79","author":"Bigalke","year":"2022","journal-title":"Hypertension"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.regpep.2004.07.010","article-title":"Expression of orexin receptors in the brain and peripheral tissues of the male sheep","volume":"124","author":"Zhang","year":"2005","journal-title":"Regul. Pept."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"997","DOI":"10.3389\/fpsyg.2014.00997","article-title":"Orexin-A controls sympathetic activity and eating behavior","volume":"5","author":"Messina","year":"2014","journal-title":"Front. Psychol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s10571-017-0487-z","article-title":"The Orexin System and Hypertension","volume":"38","author":"Huber","year":"2018","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fnins.2014.00022","article-title":"Orexin, cardio-respiratory function, and hypertension","volume":"8","author":"Li","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R1654","DOI":"10.1152\/ajpregu.00704.2005","article-title":"Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice","volume":"290","author":"Zhang","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3389\/fnins.2013.00257","article-title":"Orexin, orexin receptor antagonists and central cardiovascular control","volume":"7","author":"Carrive","year":"2013","journal-title":"Front. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.neuropharm.2015.08.012","article-title":"Upregulation of orexin receptor in paraventricular nucleus promotes sympathetic outflow in obese Zucker rats","volume":"99","author":"Zhou","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.peptides.2005.08.008","article-title":"Expression of orexin-A and orexin receptors in the kidney and the presence of orexin-A-like immunoreactivity in human urine","volume":"27","author":"Takahashi","year":"2006","journal-title":"Peptides"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3389\/fnins.2014.00057","article-title":"OX1 and OX2 orexin\/hypocretin receptor pharmacogenetics","volume":"8","author":"Thompson","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/ajmg.b.30047","article-title":"Variants of the orexin2\/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette\u2019s syndrome comorbidity","volume":"129B","author":"Thompson","year":"2004","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1002\/lary.23179","article-title":"A functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan","volume":"122","author":"Ahmed","year":"2012","journal-title":"Laryngoscope"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.psyneuen.2018.09.042","article-title":"The preliminary investigation of orexigenic hormone gene polymorphisms on posttraumatic stress disorder symptoms","volume":"100","author":"Li","year":"2019","journal-title":"Psychoneuroendocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s10194-011-0314-8","article-title":"Evidence for an association between migraine and the hypocretin receptor 1 gene","volume":"12","author":"Rainero","year":"2011","journal-title":"J. Headache Pain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e34206","DOI":"10.1097\/MD.0000000000034206","article-title":"A review of physiological functions of orexin: From instinctive responses to subjective cognition","volume":"102","author":"Xia","year":"2023","journal-title":"Medicine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"170092","DOI":"10.1016\/j.peptides.2019.170092","article-title":"Plasma orexin-A-like immunoreactivity levels and renal function in patients in a geriatric ward","volume":"118","author":"Nakashima","year":"2019","journal-title":"Peptides"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0303-7207(03)00206-5","article-title":"Orexin-A expression in human peripheral tissues","volume":"205","author":"Nakabayashi","year":"2003","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nigro, E., Mallardo, M., Amicone, M., D\u2019Arco, D., Riccio, E., Marra, M., Pasanisi, F., Pisani, A., and Daniele, A. (2024). Exploring Adiponectin in Autosomal Dominant Kidney Disease: Insight and Implications. Genes, 15.","DOI":"10.3390\/genes15040484"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s11906-018-0879-6","article-title":"Orexins, Sleep, and Blood Pressure","volume":"20","author":"Sieminski","year":"2018","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R581","DOI":"10.1152\/ajpregu.00671.2002","article-title":"Attenuated defense response and low basal blood pressure in orexin knockout mice","volume":"285","author":"Kayaba","year":"2003","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1177\/2514183X18789327","article-title":"Clinical Implications of Basic Research: The Role of Hypocretin\/Orexin Neurons in the Central Autonomic Network","volume":"2","author":"Bastianini","year":"2018","journal-title":"Clin. Transl. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1212\/WNL.0000000000000793","article-title":"Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy","volume":"83","author":"Donadio","year":"2014","journal-title":"Neurology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1159\/000054724","article-title":"Plasma orexin concentrations in patients on hemodialysis","volume":"90","author":"Sugimoto","year":"2002","journal-title":"Nephron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s10157-015-1150-y","article-title":"Messenger RNA expression profile of sleep-related genes in peripheral blood cells in patients with chronic kidney disease","volume":"20","author":"Kitajima","year":"2016","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/head.13462","article-title":"Analysis of HCRTR2 Gene Variants and Cluster Headache in Sweden","volume":"59","author":"Fourier","year":"2019","journal-title":"Headache"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1212\/01.WNL.0000142424.65251.DB","article-title":"A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache","volume":"63","author":"Rainero","year":"2004","journal-title":"Neurology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1212\/01.wnl.0000215852.35329.34","article-title":"Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene","volume":"66","author":"Kurth","year":"2006","journal-title":"Neurology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:54:23Z","timestamp":1760108063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":37,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25116243"],"URL":"https:\/\/doi.org\/10.3390\/ijms25116243","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,5]]}}}