Tamoxifen ameliorates obstructive nephropathy through Src and the PI3K/Akt/mTOR pathway
Tamoxifen ameliorates obstructive nephropathy through Src and the PI3K/Akt/mTOR pathway
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DOI：
10.1111/boc.201800040
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发表时间：
2019-01-01
影响因子：
2.7
通讯作者：
Kim, Soo Wan
中科院分区：
文献类型：
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作者：
Kim, Chang Seong;Kim, In Jin;Kim, Soo Wan
背景信息 肾小管间质纤维化是慢性肾脏疾病的终点。他莫昔芬是一种选择性雌激素受体 (ER) 调节剂，通过调节转化生长因子 (TGF)-β/Smad 信号传导来减轻肾纤维化。 Src 和磷酸肌醇 3-激酶 (PI3K)/Akt 通路在肾纤维化的发病机制中发挥着关键作用。然而，他莫昔芬治疗后肾纤维化中非典型 TGF-β 信号传导的激活仍不清楚。大鼠单侧输尿管梗阻（UUO）诱导肾纤维化。 UUO 后口服他莫昔芬。此外，在存在或不存在 TGF-β 1 的情况下，用他莫昔芬处理 HK-2 细胞。使用选择性 ER 下调剂 ICI 和 ER-α 沉默来证实 ER-α 参与他莫昔芬对 TGF-β 1 刺激的 HK-2 细胞纤维化的影响。结果 他莫昔芬治疗可改善 UUO 诱导的肾纤维化，如α-平滑肌肌动蛋白 (SMA)、纤连蛋白和结缔组织生长因子 (CTGF) 表达减少所示。在他莫昔芬治疗的动物的 UUO 肾脏中，Src、PI3K、Akt、哺乳动物雷帕霉素靶标 (mTOR) 和 p70S6K 的磷酸化显着降低。 Tamoxifen 剂量依赖性地抑制 HK-2 细胞中 TGF-β 1 诱导的 α-SMA 和 CTGF 表达以及 Src、PI3K、Akt、mTOR 和 p70S6K 的磷酸化。 ICI 治疗和 ER-α 沉默可逆转这些抗纤维化作用。此外，在用 PP1（一种 Src 激酶抑制剂）和他莫昔芬共同处理的 HK-2 细胞中观察到 PI3K/Akt 和 mTOR/p70S6K 通路受到抑制。结论 他莫昔芬的抗纤维化作用与通过 ER-α 抑制 Src 激酶功能，进而抑制 PI3K/Akt 和 mTOR/p70S6K 信号通路有关。意义我们的研究结果表明他莫昔芬是预防和治疗肾纤维化的一种新的治疗选择。
Background information Tubulointerstitial fibrosis is the end-point of chronic kidney diseases. Tamoxifen, a selective oestrogen receptor (ER) modulator, attenuates renal fibrosis, by regulating the transforming growth factor (TGF)-beta/Smad signalling. Src and phosphoinositide 3-kinase (PI3K)/Akt pathways play critical roles in the pathogenesis of renal fibrosis. However, the activation of the non-canonical TGF-beta signalling in renal fibrosis after treatment with tamoxifen remains unclear. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in rats. Tamoxifen was orally administered after UUO. Additionally, HK-2 cells were treated with tamoxifen in the presence or absence of TGF-beta 1. The selective ER down-regulator ICI and ER-alpha silencing were used to confirm the involvement of ER-alpha on the effect of tamoxifen on TGF-beta 1-stimulated fibrosis in HK-2 cells. Results Tamoxifen treatment ameliorated UUO-induced renal fibrosis as shown by decreased expression of alpha-smooth muscle actin (SMA), fibronectin and connective tissue growth factor (CTGF). The phosphorylation of Src, PI3K, Akt, mammalian target of rapamycin (mTOR) and p70S6K significantly decreased in UUO kidneys from tamoxifen-treated animals. Tamoxifen dose-dependently suppressed the TGF-beta 1-induced expression of alpha-SMA and CTGF, and phosphorylation of Src, PI3K, Akt, mTOR and p70S6K in HK-2 cells. These anti-fibrotic effects were reversed by treatment with ICI and silencing of ER-alpha. Moreover, inhibition of the PI3K/Akt and mTOR/p70S6K pathways was observed in HK-2 cells co-treated with PP1 (a Src kinase inhibitor) and tamoxifen. Conclusions The anti-fibrotic effects of tamoxifen are associated with the suppression of Src kinase function via ER-alpha, followed by inhibition of the PI3K/Akt and mTOR/p70S6K signalling pathways. Significance Our findings suggest that tamoxifen is a novel therapeutic option for the prevention and treatment of renal fibrosis.