BMP6 attenuates oxidant injury in HK-2 cells via Smad-dependent HO-1 induction

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• 作者：Jidong Yan ; Shuang Yang ; Jie Zhang ; Chunli Zhai ; Tianhui Zhu
• 关键词：Human proximal tubule cells ; Hydrogen peroxide ; Cell injury ; Bone morphogenetic protein 6 ; Smad signaling ; Heme oxygenase 1 ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2009
• 出版时间：1 May 2009
• 年：2009
• 卷：46
• 期：9
• 页码：1275-1282
• 全文大小：822 K

文摘

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.