1. IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage.
- Author
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Ren J, Lu X, Hall G, Privratsky JR, Robson MJ, Blakely RD, and Crowley SD
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Disease Models, Animal, Doxorubicin, Glomerulonephritis chemically induced, Glomerulonephritis pathology, Glomerulonephritis prevention & control, Humans, Interleukin-1beta pharmacology, Intracellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Mice, 129 Strain, Mice, Knockout, Podocytes drug effects, Podocytes pathology, Proteinuria chemically induced, Proteinuria pathology, Proteinuria prevention & control, Proto-Oncogene Proteins c-akt metabolism, Receptors, Interleukin-1 Type I agonists, Receptors, Interleukin-1 Type I genetics, Signal Transduction, Mice, Glomerulonephritis metabolism, Podocytes metabolism, Proteinuria metabolism, Receptors, Interleukin-1 Type I metabolism
- Abstract
Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease. NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.
- Published
- 2022
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