{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T06:42:55Z","timestamp":1769582575219,"version":"3.49.0"},"reference-count":57,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,5]],"date-time":"2022-11-05T00:00:00Z","timestamp":1667606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL-137004"],"award-info":[{"award-number":["HL-137004"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R24HL114474"],"award-info":[{"award-number":["R24HL114474"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DURIP 14RT0605"],"award-info":[{"award-number":["DURIP 14RT0605"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"David and Helen Boone Foundation Research Fund","award":["HL-137004"],"award-info":[{"award-number":["HL-137004"]}]},{"name":"David and Helen Boone Foundation Research Fund","award":["R24HL114474"],"award-info":[{"award-number":["R24HL114474"]}]},{"name":"David and Helen Boone Foundation Research Fund","award":["DURIP 14RT0605"],"award-info":[{"award-number":["DURIP 14RT0605"]}]},{"name":"University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center","award":["HL-137004"],"award-info":[{"award-number":["HL-137004"]}]},{"name":"University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center","award":["R24HL114474"],"award-info":[{"award-number":["R24HL114474"]}]},{"name":"University of Toledo Women and Philanthropy Genetic Analysis Instrumentation Center","award":["DURIP 14RT0605"],"award-info":[{"award-number":["DURIP 14RT0605"]}]},{"DOI":"10.13039\/100000181","name":"Air Force Office of Scientific Research","doi-asserted-by":"publisher","award":["HL-137004"],"award-info":[{"award-number":["HL-137004"]}],"id":[{"id":"10.13039\/100000181","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000181","name":"Air Force Office of Scientific Research","doi-asserted-by":"publisher","award":["R24HL114474"],"award-info":[{"award-number":["R24HL114474"]}],"id":[{"id":"10.13039\/100000181","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000181","name":"Air Force Office of Scientific Research","doi-asserted-by":"publisher","award":["DURIP 14RT0605"],"award-info":[{"award-number":["DURIP 14RT0605"]}],"id":[{"id":"10.13039\/100000181","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endogenous cardiotonic steroids (CTSs), such as telocinobufagin (TCB) and marinobufagin (MBG) contain a lactone moiety critical to their binding and signaling through the Na+\/K+-ATPase. Their concentrations elevate in response to sodium intake and under volume-expanded conditions. Paraoxonase 3 (PON3) is an enzyme that can hydrolyze lactone substrates. Here, we examine the role of PON3 in regulating CTS levels in a rat model of chronic kidney diseases (CKD). TCB and MBG were extracted from rat urine samples, and the analyses were carried out using ultra-high pressure liquid chromatography\u2013Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS). Ten-week-old Dahl salt-sensitive wild type (SS-WT) and Dahl salt-sensitive PON3 knockout (SS-PON3 KO) rats were maintained on a high-salt diet (8% NaCl) for 8 weeks to initiate salt-sensitive hypertensive renal disease characteristic of this model. CTS extraction recovery from urine &gt;80% was achieved. For animals maintained on a normal chow diet, the baseline amount of TCB excreted in 24 h urine of SS-PON3 KO rats (6.08 \u00b1 1.47 ng\/24 h; or 15.09 \u00b1 3.25 pmol) was significantly higher than for SS-WT rats (1.48 \u00b1 0.69 ng\/24 h; or 3.67 \u00b1 1.54 pmol, p &lt; 0.05). Similarly, for the same animals, the amount of excreted MBG was higher in the urine of SS-PON3 KO rats (4.74 \u00b1 1.30 ng\/24 h versus 1.03 \u00b1 0.25 ng\/24 h in SS-WT; or 11.83 \u00b1 2.91 pmol versus 2.57 \u00b1 0.56 pmol in SS-WT, p &lt; 0.05). For animals on a high-salt diet, the SS-PON3 KO rats had significantly increased levels of TCB (714.52 \u00b1 79.46 ng\/24 h; or 1774.85 \u00b1 175.55 pmol) compared to SS-WT control (343.84 \u00b1 157.54 ng\/24 h; or 854.09 \u00b1 350.02 pmol, p &lt; 0.05), and comparatively higher levels of MBG were measured for SS-PON3 KO (225.55 \u00b1 82.61 ng\/24 h; or 563.19 \u00b1 184.5 pmol) versus SS-WT (157.56 \u00b1 85.53 ng\/24 h; or 393.43 \u00b1 191.01 pmol, p &gt; 0.05) rats. These findings suggest that the presence and absence of PON3 dramatically affect the level of endogenous CTSs, indicating its potential role in CTS regulation.<\/jats:p>","DOI":"10.3390\/ijms232113565","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T08:40:16Z","timestamp":1667896816000},"page":"13565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Quantification of Cardiotonic Steroids Potentially Regulated by Paraoxonase 3 in a Rat Model of Chronic Kidney Disease Using UHPLC-Orbitrap-MS"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7622-9889","authenticated-orcid":false,"given":"Sabitri","family":"Lamichhane","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chrysan J.","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6919-6342","authenticated-orcid":false,"given":"Steven T.","family":"Haller","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5265-0142","authenticated-orcid":false,"given":"David J.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dragan","family":"Isailovic","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000363301","article-title":"The role of cardiotonic steroids in the pathogenesis of cardiomyopathy in chronic kidney disease","volume":"128","author":"Pavlovic","year":"2014","journal-title":"Nephron Clin. 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