BMP6 attenuates oxidant injury in HK-2 cells via Smad-dependent HO-1 induction.
BMP6 attenuates oxidant injury in HK-2 cells via Smad-dependent HO-1 induction.
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DOI：
10.1016/j.freeradbiomed.2009.02.007
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发表时间：
2009-05
影响因子：
7.4
通讯作者：
Ji-dong Yan;Shuang Yang;Jie Zhang;Chunli Zhai;T. Zhu
中科院分区：
文献类型：
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作者：
Ji-dong Yan;Shuang Yang;Jie Zhang;Chunli Zhai;T. Zhu
氧化应激参与多种肾脏疾病，而血红素加氧酶1(HO-1)的诱导是对氧化应激的一种保护性反应。骨形态发生蛋白6(Bmp6)的下调与宫内生长受限新生儿的肾脏损害有关。然而，Bmp6是否具有肾脏保护作用或HO-1的诱导作用尚不清楚。在这项研究中，我们证明了Bmp6有效地保护肾近端小管细胞(HK-2)免受过氧化氢(H_2O_2)诱导的细胞损伤。BMP6还可增加HO-1基因表达和HO活性。抑制De-nevo基因表达、HO抑制剂ZnPPIX、HO-1基因敲除或一氧化碳(CO)清除剂血红蛋白可减弱Bmp6的细胞保护作用，而HO-1结构性表达、HO-1诱导剂氯化血红素或氯化血红素代谢产物胆红素和一氧化碳可改善H_2O_2诱导的细胞损伤。Bmp6刺激HK-2细胞可激活Smad信号，但不能激活丝裂原激活的蛋白激酶。此外，Smad5基因敲除可抑制Bmp6诱导的HO-1表达和HO活性的增加。此外，HO-1启动子中Smad结合元件的缺失或突变也抑制了Bmp6诱导的荧光素酶活性。综上所述，这些发现表明，Bmp6通过Smad依赖机制诱导HO-1的表达是Bmp6在H_2O_2介导的肾细胞损伤中发挥细胞保护作用的原因。
Oxidative stress is involved in a variety of kidney diseases, and heme oxygenase 1 (HO-1) induction is a protective response to oxidative stress. Downregulation of bone morphogenetic protein 6 (BMP6) is associated with renal damage in intrauterine growth-restricted newborns. However, it is unknown whether BMP6 has a renoprotective effect or HO-1 induction property. In this study, we demonstrate that BMP6 effectively protects renal proximal tubule cells (HK-2) against hydrogen peroxide (H2O2)-induced cell injury. BMP6 also increased HO-1 gene expression and activity of HO. Inhibition of de novo gene expression, the HO inhibitor ZnPPIX, HO-1 knockdown, or the carbon monoxide (CO) scavenger hemoglobin attenuated the cytoprotective effect of BMP6, whereas HO-1 constitutive expression, the HO-1 inducer hemin, or the hemin metabolites bilirubin and CO ameliorated H2O2-induced cell injury. Stimulation of HK-2 cells with BMP6 activated Smad signaling but not mitogen-activated protein kinases. In addition, BMP6-mediated induction of HO-1 expression and increase in HO activity were inhibited by Smad5 knockdown. Furthermore, deletion or mutation of the Smad-binding element in the HO-1 promoter also inhibited BMP6-induced luciferase activity. In summary, these findings suggest that induction of HO-1 through a Smad-dependent mechanism is responsible for the cytoprotective effect of BMP6 in H2O2-mediated renal cell injury.