Interleukin-1β as a driver of renal NGAL production

Neutrophil gelatinase-associated lipocalin (NGAL) is increasingly regarded as a biomarker of acute kidney injury, or kidney injury in general, but the stimuli responsible for its production are incompletely understood. This study tested the relationship between the pro-inflammatory cytokine interleukin-1β (IL-1β) and both circulating and renal NGAL, using chronic subcutaneous infusion of IL-1β in mice and tissue culture of renal cell lines. Following a 14-day subcutaneous infusion of vehicle or IL-1β (10 ng/h) in male C57Bl/6 mice, a striking positive correlation (r2 = 0.94; P < 0.01) was observed between plasma IL-1β and NGAL concentrations. NGAL was markedly increased in the kidneys of IL-1β-infused mice compared with vehicle-treated mice, both at the protein and mRNA level, indicating increased local as well as systemic production of NGAL. Immunohistochemical staining revealed prominent increases of NGAL in the proximal tubular epithelium of IL-1β infused mice. These effects occurred in the absence of overt renal injury, with plasma creatinine concentration not significantly different between groups. Further showing that IL-1β has a direct effect on NGAL production by tubular epithelial cells, exposure of a proximal tubular cell line (HK-2 cells) and a cortical collecting duct principal cell line (mpkCCD cells) to IL-1β for 24 h produced a significant increase of NGAL mRNA levels (>30-fold). These data indicate IL-1β serves as a powerful stimulus for renal production of NGAL.