BMP6 attenuates oxidant injury in HK-2 cells via Smad-dependent HO-1 induction.
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 (H(2)O(2))-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 H(2)O(2)-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 H(2)O(2)-mediated renal cell injury.
Yan
Jidong
J
Medical College of Nankai University, Tianjin, China.
Yang
Shuang
S
Zhang
Jie
J
Zhai
Chunli
C
Zhu
Tianhui
T
D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics*; D025461:Feedback, Physiological; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019076:Transgenes
D055418:Bone Morphogenetic Protein 6; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D051902:Smad5 Protein; D003609:Dactinomycin; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1