FGF1ΔHBS ameliorates chronic kidney disease via PI3K/AKT mediated suppression of oxidative stress and inflammation
FGF1ΔHBS ameliorates chronic kidney disease via PI3K/AKT mediated suppression of oxidative stress and inflammation
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FGF1(Delta HBS) 通过 PI3K/AKT 介导的氧化应激和炎症抑制改善慢性肾脏疾病
DOI：
10.1038/s41419-019-1696-9
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发表时间：
2019-06-12
影响因子：
9
通讯作者：
Huang, Zhifeng
中科院分区：
文献类型：
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作者：
Wang, Dezhong;Jin, Mengyun;Huang, Zhifeng
目前，缺乏治疗具有不可逆肾功能恶化的慢性肾脏病（CKD）的有效治疗方法。本研究旨在研究突变型FGF 1（FGF 1（Delta HBS），其促有丝分裂活性降低）缓解CKD的能力，并研究其相关机制。我们发现FGF 1（Delta HBS）在肾组织中表现出比野生型FGF 1（FGF 1（WT））弱得多的促有丝分裂活性。RNA-seq分析显示，FGF 1（Delta HBS）抑制了高糖激发的小鼠足细胞中的氧化应激和炎症信号。FGF 1（Delta HBS）的这些抗氧化应激和抗炎活性在两种小鼠模型中预防了CKD：糖尿病肾病模型和阿霉素诱导的肾病模型。进一步的机制分析表明，FGF 1（Delta HBS）对氧化应激和炎症的抑制作用分别通过GSK-3 β/Nrf 2通路的激活和ASK 1/JNK信号通路的抑制介导。一项深入的研究表明，这两种途径都受到FGF 1（Delta HBS）激活的PI 3 K/AKT信号传导的控制。这一发现扩展了FGF 1（Delta HBS）用于治疗与氧化应激和炎症相关的各种CKD的潜在用途。
Currently, there is a lack of effective therapeutic approaches to the treatment of chronic kidney disease (CKD) with irreversible deterioration of renal function. This study aimed to investigate the ability of mutant FGF1 (FGF1(Delta HBS), which has reduced mitogenic activity) to alleviate CKD and to study its associated mechanisms. We found that FGF1(Delta HBS) exhibited much weaker mitogenic activity than wild-type FGF1 (FGF1(WT)) in renal tissues. RNA-seq analysis revealed that FGF1(Delta HBS) inhibited oxidative stress and inflammatory signals in mouse podocytes challenged with high glucose. These antioxidative stress and anti-inflammatory activities of FGF1(Delta HBS) prevented CKD in two mouse models: a diabetic nephropathy model and an adriamycin-induced nephropathy model. Further mechanistic analyses suggested that the inhibitory effects of FGF1(Delta HBS) on oxidative stress and inflammation were mediated by activation of the GSK-3 beta/Nrf2 pathway and inhibition of the ASK1/JNK signaling pathway, respectively. An in-depth study demonstrated that both pathways are under control of PI3K/AKT signaling activated by FGF1(Delta HBS). This finding expands the potential uses of FGF1(Delta HBS) for the treatment of various kinds of CKD associated with oxidative stress and inflammation.