Chemoprotective Mechanism of Sodium Thiosulfate Against Cisplatin-Induced Nephrotoxicity Is via Renal Hydrogen Sulfide, Arginine/cAMP and NO/cGMP Signaling Pathways
Bibliographic record
Abstract
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 µM) 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-1β, IL-6 and TNF-α and impaired renal antioxidant status compared to HC rats (p < 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 < 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 < 0.01). These functional changes worsened significantly in CIN + PAG rats (p < 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-1α. 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".