Expression of Transforming Growth Factor-β1 Limits Renal Ischemia-Reperfusion Injury
Expression of Transforming Growth Factor-β1 Limits Renal Ischemia-Reperfusion Injury
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DOI：
10.1097/tp.0b013e3181d8e9dc
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发表时间：
2010-06-15
期刊：
影响因子：
6.2
通讯作者：
Du, Caigan
中科院分区：
文献类型：
--
作者：
Guan, Qiunong;Nguan, Christopher Y. C.;Du, Caigan
背景肾缺血再灌注损伤（IRI）是导致移植肾功能障碍和急性肾损伤的重要原因，但其发病机制尚不完全清楚。在这项研究中，转化生长因子（TGF）-β 1在肾IRI的作用进行了研究，使用TGF-β 1缺陷小鼠。以人肾小管上皮细胞系（HK-2）为体外培养模型，采用流式细胞仪检测细胞凋亡。在32 ℃下夹闭小鼠肾静脉和肾动脉45 min，诱导小鼠肾IRI。在这里，我们发现，在HK-2细胞培养，TGF-β 1表达上调肿瘤坏死因子（TNF）-α。TGF-β 1活性的中和增加了自发的和TNF-α介导的凋亡，并且TGF-β 1表达的敲低增加了细胞凋亡对TNF-α的敏感性。在肾IRI的小鼠模型中，TGF-β 1表达的缺乏增加了肾损伤的严重程度，如与野生型对照组相比，TGF-β 1缺乏小鼠中更严重的肾小管损伤、更高水平的血清肌酐或血尿素氮所示。进一步的实验表明TGF-β 1的抗凋亡作用与Bcl-2的上调有关。可能由促炎性TNF-α诱导的TEC中TGF-β 1的表达使TEC对细胞死亡具有抗性。在小鼠中，TGF-β 1缺乏导致更容易发生IRI。这些数据表明，TGF-β 1可能作为一个反馈生存因子在抵抗肾损伤和维持上皮稳态。
Background. Renal ischemia-reperfusion injury (IRI) largely contributes to kidney transplant dysfunction and acute kidney injury, but its pathogenesis is not fully understood. In this study, the role of transforming growth factor (TGF)-beta 1 in renal IRI is investigated using TGF-beta 1 deficient mice.Method. Human renal tubular epithelial cells (TEC) line (HK-2) was used as an in vitro model, and cell apoptosis was determined by flow cytometric analysis. Renal IRI was induced in mice by clamping renal vein and artery for 45 min at 32 degrees C.Results. Here, we showed that in cultures of HK-2 cells, TGF-beta 1 expression was up-regulated by tumor necrosis factor (TNF)-alpha. Neutralization of TGF-beta 1 activity increased both spontaneous and TNF-alpha-mediated apoptosis, and knockdown of TGF-beta 1 expression increased the sensitivity of cell apoptosis to TNF-alpha. In a mouse model of renal IRI, a deficiency in TGF-beta expression increased the severity of renal injury, as indicated by more severe renal tubular damage, higher levels of serum creatinine or blood urea nitrogen in TGF-beta 1 deficient mice as compared with those in wild-type controls. Further experiments showed that the antiapoptosis of TGF-beta 1 correlated with up-regulation of Bcl-2 in kidney cells.Conclusion. Expression of TGF-beta 1 in TECs, potentially induced by proinflammatory TNF-alpha, renders TECs resistance to cell death. In mice, TGF-beta 1 deficiency results in more prone to IRI. These data imply that TGF-beta 1 may act as a feedback survival factor in the resistance to kidney injury and maintenance of epithelium homeostasis.