Nur77 ameliorates age-related renal tubulointerstitial fibrosis by suppressing the TGF-β/Smads signaling pathway
Nur77 ameliorates age-related renal tubulointerstitial fibrosis by suppressing the TGF-β/Smads signaling pathway
复制标题
DOI：
10.1096/fj.202101332r
复制
发表时间：
2022-02-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Difei
中科院分区：
文献类型：
--
作者：
Ma, Guojing;Chen, Feng;Wang, Difei
神经生长因子诱导的基因B（Nur 77）已被证明可以改善慢性疾病中的几种生物学过程，包括炎症反应、细胞增殖和代谢。慢性肾脏病（CKD）的特征是肾小管间质纤维化，目前尚无靶向治疗方法。在这项研究中，我们进行了体内和体外实验，以证明Nur 77靶向纤维化信号，并在衰老过程中减弱肾小管间质纤维化。我们观察到TGF-β/Smads信号通路被Nur 77显著抑制，表明Nur 77控制TGF-β/Smads信号通路中关键步骤的激活。我们进一步发现Nur 77与Smad 7相互作用，Smad 7是Smad 2/3核转位的主要阻遏物，并稳定了Smad 7蛋白的稳态。Nur 77缺陷导致Smad 7降解，加重Smad 2/3磷酸化，并促进其下游靶基因ACTA 2和胶原I的转录。我们的研究结果表明，Nur 77是包括CKD在内的年龄相关性肾脏疾病的潜在治疗靶点。Nur 77的维持治疗可能是阻断老年人肾小管间质纤维化和改善肾功能的有效策略。
Nerve growth factor-induced gene B (Nur77) has been shown to ameliorate several biological processes in chronic diseases, including inflammatory response, cellular proliferation, and metabolism. Chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis for which no targeted therapies are available as yet. In this study, we performed in vivo and in vitro experiments to demonstrate that Nur77 targets fibrosis signals and attenuates renal tubulointerstitial fibrosis during the aging process. We observed that the TGF-beta/Smads signal pathway was significantly suppressed by Nur77, suggesting that Nur77 controlled the activation of key steps in TGF-beta/Smads signaling. We further showed that Nur77 interacted with Smad7, the main repressor of nuclear translocation of Smad 2/3, and stabilized Smad7 protein homeostasis. Nur77 deficiency resulted in Smad7 degradation, aggravating Smad2/3 phosphorylation, and promoting transcription of its downstream target genes, ACTA2 and collagen I. Our findings demonstrate that Nur77 is a potential therapeutic target for age-related kidney diseases including CKD. Maintenance of Nur77 may be an effective strategy for blocking renal tubulointerstitial fibrosis and improving renal function in the elderly.