Chemoprotective Mechanism of Sodium Thiosulfate Against Cisplatin-Induced Nephrotoxicity Is via Renal Hydrogen Sulfide, Arginine/cAMP and NO/cGMP Signaling Pathways.

IF 5.6 2区 生物学 International Journal of Molecular Sciences Pub Date : 2025-01-04 DOI:10.3390/ijms26010384
George J Dugbartey, Karl K Alornyo, Ismaila Adams, Samuel Adjei, Daniel Amoah, Richard Obeng-Kyeremeh
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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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硫代硫酸钠通过肾脏硫化氢、精氨酸/cAMP和NO/cGMP信号通路抗顺铂所致肾毒性的化学保护机制
顺铂是一种常见的高效化疗药物,其肾毒性副作用已得到充分描述。硫代硫酸钠(STS)是一种经美国 FDA 批准的硫化氢(H2S)供体药物,正在成为一种针对顺铂诱导的肾毒性(CIN)的化学保护剂。在本研究中,我们研究了 STS 在大鼠 CIN 模型中的化学保护机制。25 只雄性 Sprague Dawley 大鼠被随机分配到以下组别:HC:健康对照组(腹腔注射 10 mL/kg/day 的 0.9%生理盐水腹腔注射(ip),[n = 5]),CIN:顺铂(接受单剂量 7 毫克/千克顺铂 ip [n = 5]);CIN + PAG:顺铂和每天腹腔注射 40 毫克/千克 H2S 抑制剂 DL-丙炔基甘氨酸(PAG),持续 28 天(n = 5);CIN + PAG + STS:顺铂和每日 PAG 及 STS(150 µM)ip 注射,28 天;CIN + STS:CIN + STS:顺铂和每日 STS ip 注射,28 天(n = 5)。各组大鼠在顺铂给药后的第 0、14 和 29 天分别在代谢笼中饲养 24 小时,以收集尿液。然后将大鼠安乐死,收集肾脏和血液样本进行分析。与 HC 大鼠相比,CIN 的组织学特征是肾小球和肾小管损伤,巨噬细胞大量涌入和肾小管凋亡,血浆和肾脏 IL-1β、IL-6 和 TNF-α 水平明显升高,肾脏抗氧化状态受损(p < 0.001)。与 CIN + PAG 大鼠相比,这些病理变化在 CIN + PAG 大鼠中加剧,在 CIN + PAG + STS 大鼠中则显著减少(p < 0.01),而在 CIN + STS 大鼠中则观察到较好的肾脏保护作用。在功能方面,与 HC 相比,CIN 表现为血清肌酐和 BUN 水平明显升高,尿肌酐、肾肌酐清除率以及电解质失衡和尿浓缩缺陷显著降低(p < 0.01)。这些功能变化在 CIN + PAG 大鼠中明显恶化(p < 0.05),但在 CIN + PAG + STS 大鼠中有所改善,在 CIN + STS 大鼠中进一步改善到与 HC 大鼠相当的水平。从机理上讲,STS 提高了肾脏和血浆中 H2S、精氨酸、cAMP、一氧化氮 (NO) 和 cGMP 以及 SIRT3 和 PGC-1α 的水平。我们首次证明,STS 通过激活肾精氨酸/cAMP 和 NO/cGMP 信号通路及其下游机制,增加肾 H2S 的产生,从而提供针对 CIN 的化学保护。
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期刊介绍: The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).
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