{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:13:28Z","timestamp":1768504408723,"version":"3.49.0"},"posted":{"date-parts":[[2023,3,10]]},"group-title":"Physiology","reference-count":50,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Aim<\/jats:title>\n                  <jats:p>We aimed to identify new mechanisms by which a high salt diet (HS) decreases NO production in kidney microvascular endothelial cells. Specifically, we hypothesized HS impairs NO signaling through a histone deacetylase 1 (HDAC1)-dependent mechanism.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or high salt diet (4% NaCl) for two weeks. NO signaling was assessed by measuring L-NAME induced vasoconstriction of the afferent arteriole using the blood perfused juxtamedullary nephron (JMN) preparation. In this preparation, kidneys were perfused with blood from a donor rat on a matching or different diet to that of the kidney donor. Kidney endothelial cells were isolated with magnetic activated cell sorting and HDAC1 activity was measured.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We found that HS impaired NO signaling in the afferent arteriole. This was restored by inhibition of HDAC1 with MS-275. Consistent with these findings, HDAC1 activity was increased in kidney endothelial cells. We further found the loss of NO to be dependent upon the diet of the blood donor rather than the diet of the kidney donor and the plasma from HS fed rats to be sufficient to induce dysfunction suggesting a humoral factor, we termed\n                    <jats:underline>P<\/jats:underline>\n                    lasma\n                    <jats:underline>D<\/jats:underline>\n                    erived\n                    <jats:underline>E<\/jats:underline>\n                    ndothelial-dysfunction\n                    <jats:underline>M<\/jats:underline>\n                    ediator (PDEM), mediates the endothelial dysfunction. The antioxidants, PEG-SOD and PEG-catalase, as well as the NOS cofactor, tetrahydrobiopterin, restored NO signaling.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We conclude that HS activates endothelial HDAC1 through PDEM leading to decreased NO signaling. This study provides novel insights into the molecular mechanisms by which a HS decreases renal microvascular endothelial NO signaling.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.03.08.531731","type":"posted-content","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T20:40:30Z","timestamp":1678480830000},"source":"Crossref","is-referenced-by-count":0,"title":["Endothelial Histone Deacetylase 1 Activity Impairs Kidney Microvascular NO Signaling in Rats fed a High Salt Diet"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7458-9669","authenticated-orcid":false,"given":"Luke S.","family":"Dunaway","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony K.","family":"Cook","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Botta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick A.","family":"Molina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Livius V.","family":"d\u2019Uscio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zvonimir S.","family":"Katusic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Pollock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward W.","family":"Inscho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer S.","family":"Pollock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023031314053856000_2023.03.08.531731v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1304127"},{"key":"2023031314053856000_2023.03.08.531731v1.2","doi-asserted-by":"publisher","DOI":"10.4278\/ajhp.080826-QUAN-164"},{"issue":"4","key":"2023031314053856000_2023.03.08.531731v1.3","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1159\/000492406","article-title":"Dietary Salt Intake is a Significant Determinant of Impaired Kidney Function in the General Population","volume":"43","year":"2018","journal-title":"Kidney Blood Press Res"},{"key":"2023031314053856000_2023.03.08.531731v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpu028"},{"key":"2023031314053856000_2023.03.08.531731v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)04199-4"},{"key":"2023031314053856000_2023.03.08.531731v1.6","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.236992"},{"key":"2023031314053856000_2023.03.08.531731v1.7","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01197.2011"},{"key":"2023031314053856000_2023.03.08.531731v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2013.09.004"},{"key":"2023031314053856000_2023.03.08.531731v1.9","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00040.2014"},{"key":"2023031314053856000_2023.03.08.531731v1.10","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00641.2014"},{"issue":"1","key":"2023031314053856000_2023.03.08.531731v1.11","doi-asserted-by":"crossref","first-page":"H7","DOI":"10.1152\/ajpheart.2000.279.1.H7","article-title":"Reactive oxygen species may contribute to reduced endothelium-dependent dilation in rats fed high salt","volume":"279","year":"2000","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2023031314053856000_2023.03.08.531731v1.12","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00703.2006"},{"key":"2023031314053856000_2023.03.08.531731v1.13","doi-asserted-by":"publisher","DOI":"10.1159\/000102955"},{"key":"2023031314053856000_2023.03.08.531731v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-017-0059-z"},{"key":"2023031314053856000_2023.03.08.531731v1.15","doi-asserted-by":"crossref","unstructured":"Hyndman KA , Speed JS , Mendoza LD , et al. 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