title: BMP-7 represses albumin-induced chemokine synthesis in kidney tubular epithelial cells through destabilization of NF-κB-inducing kinase.
abstract: Protein overload activates proximal tubule epithelial cells (PTECs) to release chemokines. Bone morphogenetic protein-7 (BMP-7) reduces infiltrating cells and tissue damage in acute and chronic renal injuries. The present study examines the inhibitory effect and related molecular mechanism of BMP-7 on chemokine and adhesion molecule synthesis by PTECs activated with human serum albumin (HSA). The expression profiles of chemokines and adhesion molecules in cultured human PTECs were screened by PCR array. Expression of CXCL1, CXCL2 and vascular cell adhesion protein 1 (VCAM-1) by PTECs was significantly upregulated by HSA and reduced by BMP-7. HSA activated both the canonical and noncanonical nuclear factor (NF)-κB pathways in PTECs, as indicated by the increased nuclear translocation of NF-κB p50 and p52 subunits. The nuclear translocation of NF-κB p52 was completely abrogated by BMP-7, whereas NF-κB p50 activation was only partially repressed. BMP-7 increased the expression of cellular inhibitor of apoptosis 1 (cIAP1), tumor necrosis factor receptor-associated factor (TRAF)2 and TRAF3, but not of NF-κB-inducing kinase (NIK) that was significantly upregulated by HSA. Silencing NIK recapitulated the partial inhibitory effect on HSA-induced chemokine synthesis by BMP-7. Complete abolishment of the chemokine synthesis was only achieved by including additional blockade of the NF-κB p65 translocation on top of NIK silencing. Our data suggest that BMP-7 represses the NIK-dependent chemokine synthesis in PTECs activated with HSA through blocking the noncanonical NF-κB pathway and partially interfering with the canonical NF-κB pathway.
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Ai Ing
authors.initials: AI
authors.lastname: Lim
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Wai Han
authors.initials: WH
authors.lastname: Yiu
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Ruixi
authors.initials: R
authors.lastname: Li
authors.affiliation: Nephrology Center, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong.
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Joseph C K
authors.identifier: 0000000319028495
authors.initials: JC
authors.lastname: Leung
mesh_terms: D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D042541:Intracellular Space; D007684:Kidney Tubules / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D055419:Bone Morphogenetic Protein 7; D018925:Chemokines; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase