Recent advances in the understanding and management of IgA nephropathy [version 1; referees: 3 approved]

Since its first description in 1968, IgA nephropathy has remained the most common form of primary glomerulonephritis leading to chronic kidney disease in developed countries. The clinical progression varies, and consequent end-stage renal disease occurs in 30% to 40% of patients 20 to 30 years after the first clinical presentation. Current data implicate overproduction of aberrantly glycosylated IgA1 as being pivotal in the induction of renal injury. Effective and specific treatment is still lacking, and new therapeutic approaches will be developed after better understanding the disease pathogenesis

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

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-κB, and the p65/p50 subunits were activated. NF-κB activation and IL-8 secretion were attenuated by the NF-κB inhibitors pyrrolidine dithiocarbamate and cell-permeable peptide. Albumin upregulated intracellular reactive oxygen species (ROS) generation, while exogenous H(2)O(2) stimulated NF-κB translocation and IL-8 secretion. Albumin-induced ROS generation, NF-κB 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-κB–dependent pathways through PKC activation and ROS generation