Interleukin-4 and interleukin-13 act on glomerular visceral epithelial cells

In minimal change nephrosis (MCN), proteinuria is associated with structura l changes of the glomerular visceral epithelial cells (GVEC). The occurrenc e of MCN has been associated with T-helped lymphocyte-dependent conditions. To examine a direct role for type 2 cytokines in GVEC injury, the expressi on of interleukin (IL)-4/IL-13 receptors by GVEC and direct effects of IL-4 and IL-13 on GVEC were studied. Reverse transcription-PCR showed that isol ated human and rat glomeruli and cultured human and rat GVEC expressed mRNA for IL-4R alpha, IL-13R alpha 1, and IL-13R alpha 2. Protein expression of IL-4R alpha and IL-13R alpha 2 by GVEC in human kidney biopsies and by cul tured human GVEC was detected by immunohistochemistry. Western blotting dem onstrated phosphorylation of STAT6 in cultured GVEC upon incubation with IL -4 or IL-13. This indicated signal transduction via the heterodimeric recep tor complex IL-4R2, which is composed of the IL-4R alpha and the IL-13R alp ha 1. Direct effects on GVEC function were examined in monolayer experiment s. IL-4 and IL-13 dose-dependently decreased transepithelial electrical res istance of monolayers of rat GVEC to approximately 30 and 40% of baseline v alues, respectively. The transepithelial electrical resistance decrease was associated with a significant increase in short-circuit current, whereas n o changes were observed in the transmonolayer flux of the macromolecules ho rseradish peroxidase (molecular weight, 44 kD) and C-14-mannitol (molecular weight, 182 Da). No changes in cell structure were observed with electron microscopy. It is concluded that by binding to specific IL-4/IL-13 receptor s, IL-4 and IL-13 can exert specific effects on GVEC function, which could be of pathogenetic relevance for glomerular injury in MCN.