Conditional knockout of TGF-βRII/Smad2 signals protects against acute renal injury by alleviating cell necroptosis, apoptosis and inflammation
Conditional knockout of TGF-βRII/Smad2 signals protects against acute renal injury by alleviating cell necroptosis, apoptosis and inflammation
复制标题
条件性敲除 TGF-β RII/Smad2 信号可通过减轻细胞坏死性凋亡、细胞凋亡和炎症来预防急性肾损伤
DOI：
10.7150/thno.35686
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Lan, Hui Yao
中科院分区：
文献类型：
--
作者：
Yang, Qin;Ren, Gui-ling;Lan, Hui Yao
理由：tgf - β /Smad信号是肾纤维化的中心介质，然而，其在急性肾损伤（AKI）中的功能作用尚不完全清楚。我们之前发现Smad2通过限制Smad3信号传导来防止肾纤维化，但其在急性期的作用细节尚不清楚。最近的证据表明，tgf - β /Smad3可能参与AKI的发病机制，因此我们假设Smad2可能因其对程序性细胞死亡的潜在影响而在AKI中发挥一定作用。方法：建立顺铂诱导的肾小管上皮细胞（tec）特异性缺失tgf - β II型受体或Smad2的AKI小鼠模型。我们还在人HK2细胞中建立了稳定的Smad2敲低或过表达的体外模型。重要的是，我们通过在体内沉默Smad2来评估Smad2是否可以作为顺铂和缺血/再灌注（I/R）诱导的AKI小鼠模型的治疗靶点。结果：结果显示tgf - β II型受体的破坏抑制Smad2/3的激活，减轻顺铂肾病的肾损伤。此外，我们发现有条件地敲除TECs中下游Smad2可以防止肾功能丧失，并减轻顺铂肾病中p53介导的细胞凋亡、ripk介导的坏死坏死和p65 nf - κ b驱动的肾脏炎症。在顺铂处理的Smad2敲低和过表达的HK2细胞中进一步证实了这一点。此外，在已建立的肾毒性和缺血性AKI模型中，慢病毒介导的Smad2敲低可以保护肾脏免受损伤和炎症，同时恢复肾功能。结论：这些发现表明Smad2不同于其在肾纤维化中的保护作用，它通过诱导程序性细胞死亡和炎症促进AKI。这可能为急性肾损伤提供新的治疗靶点。
Rationale: TGF-beta/Smad signaling is the central mediator for renal fibrosis, however, its functional role in acute kidney injury (AKI) is not fully understood. We previously showed Smad2 protects against renal fibrosis by limiting Smad3 signaling, but details on its role in acute phase are unclear. Recent evidence showed that TGF-beta/Smad3 may be involved in the pathogenesis of AKI, so we hypothesized that Smad2 may play certain roles in AKI due to its potential effect on programmed cell death.Methods: We established a cisplatin-induced AKI mouse model with TGF-beta type II receptor or Smad2 specifically deleted from renal tubular epithelial cells (TECs). We also created stable in vitro models with either Smad2 knockdown or overexpression in human HK2 cells. Importantly, we evaluated whether Smad2 could serve as a therapeutic target in both cisplatin- and ischemic/reperfusion (I/R)-induced AKI mouse models by silencing Smad2 in vivo.Results: Results show that disruption of TGF-beta type II receptor suppressed Smad2/3 activation and attenuated renal injury in cisplatin nephropathy. Furthermore, we found that conditional knockout of downstream Smad2 in TECs protected against loss of renal function, and alleviated p53-mediated cell apoptosis, RIPK-mediated necroptosis and p65 NF-kappa B-driven renal inflammation in cisplatin nephropathy. This was further confirmed in cisplatin-treated Smad2 knockdown and overexpression HK2 cells. Additionally, lentivirus-mediated Smad2 knockdown protected against renal injury and inflammation while restoring renal function in established nephrotoxic and ischemic AKI models.Conclusions: These findings show that unlike its protective role in renal fibrosis, Smad2 promoted AKI by inducing programmed cell death and inflammation. This may offer a novel therapeutic target for acute kidney injury.