{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:24:51Z","timestamp":1790882691459,"version":"4.1.0"},"reference-count":81,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,4]],"date-time":"2025-01-04T00:00:00Z","timestamp":1735948800000},"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>Cisplatin is a common and highly effective chemotherapeutic agent whose nephrotoxic side effect is well-characterized. Sodium thiosulfate (STS), an FDA-approved hydrogen sulfide (H2S) donor drug, is emerging as a chemoprotective agent against cisplatin-induced nephrotoxicity (CIN). In this study, we investigated the chemoprotective mechanism of STS in a rat model of CIN. Twenty-five male Sprague Dawley rats were randomly assigned to the following groups: HC: Healthy control (received 10 mL\/kg\/day of 0.9% saline intraperitoneally (ip), [n = 5]), CIN: Cisplatin (received single dose of 7 mg\/kg cisplatin ip [n = 5]); CIN + PAG: Cisplatin and daily ip administration of 40 mg\/kg of the H2S inhibitor, DL-propargylglycine (PAG) for 28 days (n = 5); CIN + PAG + STS: Cisplatin and daily PAG and STS (150 \u00b5M) ip injection for 28 days; CIN + STS: Cisplatin and daily STS ip administration for 28 days (n = 5). Rats in each group were kept in metabolic cages for 24 h on day 0, 14 and 29 after cisplatin administration for urine collection. Rats were then euthanized, and kidney and blood samples were collected for analysis. Histologically, CIN was characterized by glomerular and tubular injury and significant macrophage influx and tubular apoptosis, as well as markedly increased levels of plasma and renal IL-1\u03b2, IL-6 and TNF-\u03b1 and impaired renal antioxidant status compared to HC rats (p &lt; 0.001). These pathological changes were exacerbated in CIN + PAG rats and were strongly reduced in CIN + PAG + STS rats relative to CIN + PAG rats (p &lt; 0.01), while superior renal protection was observed in CIN + STS rats. Functionally, CIN was evidenced by markedly increased levels of serum creatinine and BUN, and significantly decreased urine creatinine, renal creatinine clearance, as well as electrolyte imbalance and urinary concentrating defect in comparison with HC (p &lt; 0.01). These functional changes worsened significantly in CIN + PAG rats (p &lt; 0.05) but improved in CIN + PAG + STS rats, with further improvement in CIN + STS rats to levels comparable to HC rats. Mechanistically, STS increased renal and plasma levels of H2S, arginine, cAMP, nitric oxide (NO) and cGMP as well as SIRT3 and PGC-1\u03b1. We have shown for the first time that STS provides chemoprotection against CIN by activating renal arginine\/cAMP and NO\/cGMP signaling pathways and their downstream mechanisms through increased renal H2S production.<\/jats:p>","DOI":"10.3390\/ijms26010384","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T08:08:52Z","timestamp":1736150932000},"page":"384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Chemoprotective Mechanism of Sodium Thiosulfate Against Cisplatin-Induced Nephrotoxicity Is via Renal Hydrogen Sulfide, Arginine\/cAMP and NO\/cGMP Signaling Pathways"],"prefix":"10.3390","volume":"26","author":[{"given":"George J.","family":"Dugbartey","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra P.O. Box LG43, Ghana"},{"name":"Department of Physiology and Pharmacology, Accra College of Medicine, Accra P.O. Box CT9828, Ghana"},{"name":"Department of Surgery, Division of Urology, London Health Sciences Center, Western University, London, ON N6A 5C1, Canada"},{"name":"Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl K.","family":"Alornyo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Accra P.O. Box LG43, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7113-3888","authenticated-orcid":false,"given":"Ismaila","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology, University of Ghana Medical School, Accra P.O. Box KB52, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5954-908X","authenticated-orcid":false,"given":"Samuel","family":"Adjei","sequence":"additional","affiliation":[{"name":"Department of Animal Experimentation, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra P.O. Box LG581, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Amoah","sequence":"additional","affiliation":[{"name":"Department of Animal Experimentation, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra P.O. Box LG581, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6772-1556","authenticated-orcid":false,"given":"Richard","family":"Obeng-Kyeremeh","sequence":"additional","affiliation":[{"name":"Department of Animal Experimentation, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Accra P.O. Box LG581, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/222385a0","article-title":"Platinum compounds: A new class of potent antitumour agents","volume":"222","author":"Rosenberg","year":"1969","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chirino, Y.I., Hern\u00e1ndez-Pando, R., and Pedraza-Chaverr\u00ed, J. (2004). 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