Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo

被引:117
作者
Tang, S
Leung, JC
Abe, K
Chan, KW
Chan, LYY
Chan, TM
Lai, KN
机构
[1] Univ Hong Kong, Queen Mary Hosp, Dept Med, Div Nephrol, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Queen Mary Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China
[3] Nagasaki Univ, Sch Med, Dept Internal Med 2, Div Nephrol, Nagasaki 852, Japan
关键词
D O I
10.1172/JCI200316079
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Renal tubulointerstitial injury is characterized by inflammatory cell infiltrate; however, the stimuli for leukocyte recruitment are not fully understood. IL-8 is a potent chemokine produced by proximal tubular epithelial cells (PTECs). Whether nephrotic proteins stimulate tubular IL-8 expression remains unknown. Acute exposure of human PTECs to albumin induced IL-8 gene and protein expression time- and dose-dependently. Apical albumin predominantly stimulated basolateral IL-8 secretion. Electrophoretic mobility shift assay demonstrated nuclear translocation of NF-kappaB, and the p65/p50 subunits were activated. NF-kappaB activation and IL-8 secretion were attenuated by the NF-kappaB inhibitors pyrrolidine dithiocarbamate and cell-permeable peptide. Albumin upregulated intracellular reactive oxygen species (ROS) generation, while exogenous H2O2 stimulated NF-kappaB translocation and IL-8 secretion. Albumin-induced ROS generation, NF-kappaB activation, and IL-8 secretion were endocytosis- and PKC-dependent as these downstream events were abrogated by the PI3K inhibitors LY294002 and wortmannin, and the PKC inhibitors GF109203X and staurosporin, respectively. In vivo, IL-8 mRNA expression was localized by in situ hybridization to the proximal tubules in nephrotic kidney tissues. The intensity of IL-8 immunostaining was higher in nephrotic than non-nephrotic subjects. In conclusion, albumin is a strong stimulus for tubular IL-8 expression, which occurs via NF-kappaB-dependent pathways through PKC activation and ROS generation.
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页码:515 / 527
页数:13
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