Tubular expression of the cell-surface adhesion molecule CD44 is upregulated in both human and experimental glomerulonephritis, and this is associated with interstitial leucocytic infiltration. However, we know little of the mechanisms by which renal CD44 expression is upregulated in disease. This study focuses on the potential role of the proinflammatory cytokine interleukin 1 (IL-1) and the IL-1-inducible transcription factor early growth response factor-1 (Egr-1) on tubular CD44 expression in vivo and in vitro. Immunostaining identified constitutive CD44 expression by occasional glomerular cells and a small number of cortical tubules in normal rat kidney. Glomerular and tubular CD44 expression was markedly upregulated in rat crescentic anti-glomerular basement membrane glomerulonephritis. Blocking IL-1 activity by administration of the IL-1 receptor antagonist significantly reduced glomerular and tubular CD44 expression in this disease model. In vitro studies found that the NRK52E rat tubular epithelial cell line constitutively expresses CD44 mRNA and protein. Stimulation with 10 U/mL IL-1 caused upregulation in both CD44 mRNA and protein expression. A role for the transcription factor Egr-1 in this process was suggested by a time course study in which IL-1 stimulation of NRK52E cells caused a rapid and transient increase in Egr-1 mRNA, peaking at 30-60 min, which preceded the increase in CD44 mRNA that was evident at 3-6 h. A direct link between Egr-1 and CD44 expression was provided by the ability of an Egr-1 antisense oligonucleotide, but not sense or scrambled control oligonucleotides, to inhibit IL-1-induced upregulation of CD44 protein in NRK52E cells. These data demonstrate that IL-1 is an important stimulus for upregulation of tubular CD44 expression in vivo and in vitro. Furthermore, in vitro studies have shown that IL-1-induced upregulation of CD44 expression operates, at least in part, via the transcription factor Egr-1.
- Gene expression
- Interleukin 1