Interleukin-4 and -13 promote basolateral secretion of H(+) and cathepsin L by glomerular epithelial cells
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Published on: November 10, 2021
José G Van Den Berg1, Jan Aten, Carla Annink
1Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. j.g.vandenberg@amc.uva.nl
Abstract:
Minimal change nephrosis (MCN) is characterized by massive proteinuria and ultrastructural alterations of glomerular visceral epithelial cells (GVEC). MCN has been associated with elevated production of interleukin (IL)-13 by circulating T lymphocytes and with T helper 2 lymphocyte-dependent conditions. We recently showed that GVEC express IL-4 and IL-13 receptors and that IL-4 and IL-13 increase transcellular ion transport over GVEC monolayers. We therefore hypothesized that IL-13 may directly injure GVEC. Here we demonstrate that IL-4 and IL-13 induce bafilomycin A1-sensitive basolateral proton secretion by cultured GVEC, indicating involvement of vacuolar H(+)-ATPase. The effects of IL-4 and IL-13 were accompanied by redistribution of the small GTPases Rab5b and Rab7, as shown by confocal immunofluorescence studies. Furthermore, Western blot analysis and assays for cysteine proteinase activity revealed basolateral secretion of the lysosomal proteinase procathepsin L by cultured GVEC, stimulated by IL-4 and IL-13. We speculate that IL-4 and IL-13 influence intracellular trafficking of proteins and promote proteolysis at the basolateral surface of GVEC, which may play a pathogenic role in altered glomerular permeability.
Insights
Interleukin-13 (IL-13) may directly injure glomerular visceral epithelial cells (GVEC) in minimal change nephrosis (MCN). This study shows IL-13 induces proton secretion and proteinase release from GVEC, potentially altering glomerular permeability.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Minimal change nephrosis (MCN) involves proteinuria and glomerular visceral epithelial cell (GVEC) damage.
- Elevated interleukin (IL)-13 production is linked to MCN and T helper 2 cell activity.
- GVEC express IL-4 and IL-13 receptors, and these cytokines affect ion transport.
Purpose of the Study:
- To investigate if IL-13 directly injures GVEC.
- To elucidate the cellular mechanisms underlying IL-13-induced GVEC alterations.
Main Methods:
- Cultured GVEC were treated with IL-4 and IL-13.
- Assessed basolateral proton secretion using bafilomycin A1.
- Examined intracellular trafficking of Rab5b and Rab7 via immunofluorescence.
- Analyzed basolateral secretion of procathepsin L using Western blot and enzyme activity assays.
Main Results:
- IL-4 and IL-13 induced bafilomycin A1-sensitive proton secretion by GVEC, implicating vacuolar H(+)-ATPase.
- These cytokines caused redistribution of Rab5b and Rab7.
- IL-4 and IL-13 stimulated the basolateral secretion of procathepsin L, a lysosomal proteinase.
Conclusions:
- IL-4 and IL-13 directly affect GVEC function.
- These cytokines appear to alter intracellular protein trafficking and promote basolateral proteolysis.
- These mechanisms may contribute to the pathogenesis of altered glomerular permeability in MCN.
