Inhibition of hydrogen sulphide formation reduces cisplatin-induced renal damage
Inhibition of hydrogen sulphide formation reduces cisplatin-induced renal damage
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DOI：
10.1093/ndt/gfq447
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发表时间：
2011-02-01
影响因子：
6.1
通讯作者：
Coimbra, Terezila Machado
中科院分区：
文献类型：
--
作者：
Francescato, Heloisa Della Coletta;Cunha, Fernando Queiroz;Coimbra, Terezila Machado
背景。顺铂 (CP) 引起的肾损伤与炎症有关。硫化氢 (H2S) 参与炎症模型。本研究评估了 DL-炔丙基甘氨酸 (PAG)（一种内源性 H2S 形成抑制剂）对 CP 引起的肾损伤的影响。方法。大鼠注射 CP（5 mg/kg，腹腔注射）或 PAG（5 mg/kg，每天两次，腹腔注射）4 天，从 CP 注射前 1 小时开始。对照大鼠仅注射 0.15 M NaCl 或 PAG。注射盐水或CP后5天收集血液和尿液样本用于肾功能评估。取出肾脏进行肿瘤坏死因子 (TNF)-α 定量、组织学、免疫组织化学和蛋白质印迹分析。评估了胱硫醚γ-裂解酶（CSE）的活性和表达。通过将肾小管细胞与 NaHS（H2S 的供体）一起孵育来评估 H2S 对肾小管细胞的直接毒性。结果。 CP治疗的大鼠血浆肌酐水平以及钠和钾的排泄分数增加，这与外髓质的肾小管间质病变有关。在注射 CP 的大鼠的外髓质中也观察到 TNF-α、巨噬细胞、中性粒细胞和 T 淋巴细胞表达增加，与 H2S 形成率和 CSE 表达增加相关。所有这些改变均通过 PAG 治疗而减少。未观察到NaHS对肾小管上皮细胞的直接毒性。结论。 PAG 治疗可减少 CP 引起的肾损伤。这种作用似乎与 PAG+CP 治疗大鼠肾脏中 H2S 的形成和炎症的限制有关。
Background. Cisplatin (CP)-induced renal damage is associated with inflammation. Hydrogen sulphide (H2S) is involved in models of inflammation. This study evaluates the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by CP.Methods. The rats were injected with CP (5 mg/kg, i.p.) or PAG(5 mg/kg twice a day, i.p.) for 4 days, starting 1 h before CP injection. Control rats were injected with 0.15 M NaCl or PAG only. Blood and urine samples were collected 5 days after saline or CP injections for renal function evaluation. The kidneys were removed for tumour necrosis factor (TNF)-alpha quantification, histological, immunohistochemical and Western blot analysis. The cystathionine gamma-lyase (CSE) activity and expression were assessed. The direct toxicity of H2S in renal tubular cells was evaluated by the incubation of these cells with NaHS, a donor of H2S.Results. CP-treated rats presented increases in plasma creatinine levels and in sodium and potassium fractional excretions associated with tubulointerstitial lesions in the outer medulla. Increased expression of TNF-alpha, macrophages, neutrophils and T lymphocytes, associated with increased H2S formation rate and CSE expression, were also observed in the outer medulla from CP-injected rats. All these alterations were reduced by treatment with PAG. A direct toxicity of NaHS for renal tubular epithelial cells was not observed.Conclusions. Treatment with PAG reduces the renal damage induced by CP. This effect seems to be related to the H2S formation and the restriction of the inflammation in the kidneys from PAG+CP-treated rats.