Aberrantly glycosylated IgG elicits pathogenic signaling in podocytes and signifies lupus nephritis
| Autor: | George C. Tsokos, Rhea Bhargava, Kayaho Maeda, Isaac E. Stillman, Maria Tsokos, Sylvain Lehoux, Suzanne Krishfield, Martin R. Pollak, Richard D. Cummings, Lena Ellezian |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Glycosylation Lupus nephritis Glycobiology Autoimmunity medicine.disease_cause Podocyte Pathogenesis Mice 0302 clinical medicine Medicine Kidney biology Podocytes NF-kappa B General Medicine Middle Aged Lupus Nephritis medicine.anatomical_structure 030220 oncology & carcinogenesis Slit diaphragm Female Nephritis Research Article Adult Adolescent Immunology Immunoglobulins Cell Line Nephrin Young Adult 03 medical and health sciences Animals Humans Aged Fucose business.industry Galactose Membrane Proteins Calcium signaling medicine.disease 030104 developmental biology Immunoglobulin G biology.protein Cancer research Snail Family Transcription Factors business Calcium-Calmodulin-Dependent Protein Kinase Type 4 |
| Zdroj: | JCI Insight JCI Insight, Vol 6, Iss 9 (2021) |
| ISSN: | 2379-3708 |
| Popis: | Lupus nephritis (LN) is a serious complication occurring in 50% of patients with systemic lupus erythematosus (SLE) for which there is a lack of biomarkers, a lack of specific medications, and a lack of a clear understanding of its pathogenesis. The expression of calcium/calmodulin kinase IV (CaMK4) is increased in podocytes of patients with LN and lupus-prone mice, and its podocyte-targeted inhibition averts the development of nephritis in mice. Nephrin is a key podocyte molecule essential for the maintenance of the glomerular slit diaphragm. Here, we show that the presence of fucose on N-glycans of IgG induces, whereas the presence of galactose ameliorates, podocyte injury through CaMK4 expression. Mechanistically, CaMK4 phosphorylates NF-κB, upregulates the transcriptional repressor SNAIL, and limits the expression of nephrin. In addition, we demonstrate that increased expression of CaMK4 in biopsy specimens and in urine podocytes from people with LN is linked to active kidney disease. Our data shed light on the role of IgG glycosylation in the development of podocyte injury and propose the development of “liquid kidney biopsy” approaches to diagnose LN. |
| Databáze: | OpenAIRE |
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