Interleukin-4 and interleukin-13 act on glomerular visceral epithelial cells.
In minimal change nephrosis (MCN), proteinuria is associated with structural changes of the glomerular visceral epithelial cells (GVEC). The occurrence of MCN has been associated with 2 lymphocyte-dependent conditions. To examine a direct role for type 2 cytokines in GVEC injury, the expression 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 isolated human and rat glomeruli and cultured human and rat GVEC expressed mRNA for IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2. Protein expression of [L-4Ralpha and IL-13Ralpha2 by GVEC in human kidney biopsies and by cultured human GVEC was detected by immunohistochemistry. Western blotting demonstrated phosphorylation of STAT6 in cultured GVEC upon incubation with IL-4 or IL-13. This indicated signal transduction via the heterodimeric receptor complex IL-4R2, which is composed of the IL-4Ralpha and the IL-13Ralpha1. Direct effects on GVEC function were examined in monolayer experiments. IL-4 and IL-13 dose-dependently decreased transepithelial electrical resistance of monolayers of rat GVEC to approximately 30 and 40% of baseline values, respectively. The transepithelial electrical resistance decrease was associated with a significant increase in short-circuit current, whereas no changes were observed in the transmonolayer flux of the macromolecules horseradish peroxidase (molecular weight, 44 kD) and 14C-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 receptors, IL-4 and IL-13 can exert specific effects on GVEC function, which could be of pathogenetic relevance for glomerular injury in MCN.
VAN DEN Berg
José G
JG
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Aten
Jan
J
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Chand
M Anwar
MA
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Claessen
Nike
N
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Dijkink
Lisette
L
Department of Cell Physiology, University of Nijmegen, The Netherlands.
Wijdenes
John
J
Diaclone, Besançon, France.
Lakkis
Fadi G
FG
Renal Division, Emory University School of Medicine and Veterans Affair Medical Center, Atlanta, Georgia.
Weening
Jan J
JJ
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
D000818:Animals; D002460:Cell Line; D004553:Electric Conductivity; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D046911:Macromolecular Substances; D010539:Permeability; D010766:Phosphorylation; D051381:Rats; D018123:Receptors, Interleukin / Q000378:metabolism; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
C508181:IL13RA1 protein, human; C508185:Il13ra1 protein, rat; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D046911:Macromolecular Substances; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D007770:L-Lactate Dehydrogenase