AIMS Cisplatin (CDDP) is an effective antineoplastic agent, however, its serious nephrotoxicity limits therapeutic use. Human growth hormone (hGH) has proved antioxidant and anti-inflammatory activities. The present study aimed to investigate the nephroprotective effects of hGH against CDDP-induced nephrotoxicity and the mechanisms underlying this nephroprotection. MAIN METHODS Male albino rats injected with CDDP (7 mg/kg) and nephrotoxicity indices, oxidative stress and inflammatory biomarkers (high mobility group box protein-1 (HMGB-1), soluble epoxide hydrolase (sEH), and nuclear factor-kappa B (NF-κB)) were assessed. Also, insulin-like growth factor-1 (IGF-1) and Nuclear factor-erythroid-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway were assessed. KEY FINDINGS hGH (1 mg/kg) improved kidney function and antioxidant systems and showed intact renal tubular epithelium. Cisplatin upregulated the HMGB-1/NF-κB and downregulated Nrf2/HO-1 pathways which were reversed by hGH and aligned with increased renal IGF-1 expression. Also, IGF-1/sEH crosstalk might be involved in hGH nephroprotection. Moreover, hGH downregulated HSP70 and caspase-3 expressions. SIGNIFICANCE these results concluded that hGH can attenuate the inflammation and oxidative stress attained by CDDP probably through inhibition of Nrf2/HO-1 pathway. We also suggested that Keap1/Nrf2-mediated upregulation of the antioxidant HO-1 might inhibit HMGB-1/NF-κB signaling and thus provide the principal protection mechanism offered by hGH against CDDP-induced kidney injury.

中文翻译：

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在顺铂诱导的肾毒性中保护生长激素的新见解：IGF-1对Keap1-Nrf2 / HO-1信号的影响。

AIMS顺铂（CDDP）是一种有效的抗肿瘤药，但其严重的肾毒性限制了其治疗用途。人类生长激素（hGH）已被证明具有抗氧化和抗炎作用。本研究旨在研究hGH对CDDP诱导的肾毒性的肾保护作用以及这种肾保护作用的机制。主要方法雄性白化病大鼠注射CDDP（7 mg / kg）并具有肾毒性指数，氧化应激和炎性生物标志物（高迁移率族盒蛋白1（HMGB-1），可溶性环氧化物水解酶（sEH）和核因子-κB （NF-κB））进行评估。此外，评估了胰岛素样生长因子-1（IGF-1）和核因子-类红血球-2（Nrf2）/血红素加氧酶-1（HO-1）途径。主要发现hGH（1 mg / kg）改善了肾功能和抗氧化系统，并显示出完整的肾小管上皮。顺铂上调HMGB-1 /NF-κB并下调Nrf2 / HO-1通路，hGH逆转了该通路，并与肾脏IGF-1表达增加相吻合。同样，IGF-1 / sEH串扰可能与hGH的肾保护有关。此外，hGH下调了HSP70和caspase-3的表达。这些结果表明，hGH可能通过抑制Nrf2 / HO-1途径减轻CDDP所引起的炎症和氧化应激。我们还建议，Keap1 / Nrf2介导的抗氧化剂HO-1上调可能抑制HMGB-1 /NF-κB信号传导，从而提供hGH提供的针对CDDP诱导的肾损伤的主要保护机制。顺铂上调HMGB-1 /NF-κB并下调Nrf2 / HO-1通路，这些通路被hGH逆转并与肾脏IGF-1表达增加对齐。同样，IGF-1 / sEH串扰可能与hGH的肾保护有关。此外，hGH下调了HSP70和caspase-3的表达。这些结果表明，hGH可能通过抑制Nrf2 / HO-1途径减轻CDDP所引起的炎症和氧化应激。我们还建议，Keap1 / Nrf2介导的抗氧化剂HO-1上调可能抑制HMGB-1 /NF-κB信号传导，从而提供hGH提供的针对CDDP诱导的肾损伤的主要保护机制。顺铂上调HMGB-1 /NF-κB并下调Nrf2 / HO-1通路，hGH逆转了该通路，并与肾脏IGF-1表达增加相吻合。同样，IGF-1 / sEH串扰可能与hGH的肾保护有关。此外，hGH下调了HSP70和caspase-3的表达。这些结果表明，hGH可能通过抑制Nrf2 / HO-1途径减轻CDDP所引起的炎症和氧化应激。我们还建议，Keap1 / Nrf2介导的抗氧化剂HO-1上调可能抑制HMGB-1 /NF-κB信号传导，从而提供hGH提供的针对CDDP诱导的肾损伤的主要保护机制。hGH下调了HSP70和caspase-3的表达。这些结果表明，hGH可能通过抑制Nrf2 / HO-1途径减轻CDDP引起的炎症和氧化应激。我们还建议，Keap1 / Nrf2介导的抗氧化剂HO-1上调可能抑制HMGB-1 /NF-κB信号传导，从而提供hGH提供的针对CDDP诱导的肾损伤的主要保护机制。hGH下调了HSP70和caspase-3的表达。这些结果表明，hGH可能通过抑制Nrf2 / HO-1途径减轻CDDP所引起的炎症和氧化应激。我们还建议，Keap1 / Nrf2介导的抗氧化剂HO-1上调可能抑制HMGB-1 /NF-κB信号传导，从而提供hGH提供的针对CDDP诱导的肾损伤的主要保护机制。