Cellular inhibitor of apoptosis protein 1 (cIAP1) represses albumin-induced chemokines and adhesion molecules synthesis by kidney tubular epithelial cells

Abstract

BACKGROUND: Protein overload activates proximal tubule epithelial cells (PTEC) to release chemokines and stimulates inflammatory response in the interstitium. Bone morphogenic protein-7 (BMP-7) has been shown to reduce infiltrating cells and kidney damage in acute and chronic renal failure. The present study examines the inhibitory effects and the relevant molecular mechanism of BMP-7 on chemokines and adhesion molecules synthesis by PTEC activated with human serum albumin (HSA). METHODS: PCR array was used to screen the expression profiles of chemokines and adhesion molecules in cultured human PTEC. The molecules that were upregulated by HSA and can be significantly reduced by BMP-7 were identified. The kinetic of their expression in PTEC was determined by RT-PCR and ELISA. The activation of NF-κB and the relevant molecules of the signaling pathways were examined by RT-PCR, western blotting, immunofluorescence microscopy and transcriptional factors ELISA. RESULTS: Expression of CXCL1, CXCL2 and VCAM-1 by PTEC was upregulated by HSA, and the expression was significantly reduced by BMP-7. Further experiments confirm that BMP-7 reduced the HSA up-regulated gene and protein expression of CXCL1, CXCL2 and VCAM-1 dose and time dependently. HSA activated both the canonical and noncanonical NF-κB pathways in PTEC, as shown by the reduced expression of IκB, the nuclear translocation of p50 and p52, and data from the transcriptional factor ELISA. The NF-κB activation was repressed by BMP-7. Interestingly, the HSA-upregulated expression of cIAP1 and TRAF3 by PTEC, was further increased by BMP-7. To the contrary, the expression of NIK in PTEC was increased by HSA but down-regulated by BMP-7. CONCLUSIONS: Our data suggest that HSA up-regulates CXCL1, CXCL2 and VCAM-1 via both the canonical and noncanonical NF-κB pathways in PTEC. BMP-7 suppresses these events through increased production of cIAP-1 and TRAF3, which inhibits the accumulation of NIK and the subsequent activation of NF-κB pathways.