Aberrantly glycosylated IgG elicits pathogenic signaling in podocytes and signifies lupus nephritis
Rhea Bhargava, … , Richard D. Cummings, George C. Tsokos
Rhea Bhargava, … , Richard D. Cummings, George C. Tsokos
Published March 30, 2021
Citation Information: JCI Insight. 2021;6(9):e147789. https://doi.org/10.1172/jci.insight.147789.
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Research Article Immunology

Aberrantly glycosylated IgG elicits pathogenic signaling in podocytes and signifies lupus nephritis

Abstract

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.

Authors

Rhea Bhargava, Sylvain Lehoux, Kayaho Maeda, Maria G. Tsokos, Suzanne Krishfield, Lena Ellezian, Martin Pollak, Isaac E. Stillman, Richard D. Cummings, George C. Tsokos

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Figure 2

Treatment of IgG with α-fucosidase prevents the upregulation of CaMK4 in podocytes.

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Treatment of IgG with α-fucosidase prevents the upregulation of CaMK4 in...
(A) Both deglycosylated (Degly) and untreated IgG from individuals with LN colocalize with neonatal Fc receptor (FcRn) in human podocytes (original magnification, 200×). (B) Intensity of Alexa Fluor–tagged PNGase F–treated (deglycosylated) and untreated LN-derived IgG in podocytes was analyzed by immunofluorescence staining (20×). (C) CaMK4 expression was evaluated after exposure of podocytes to deglycosylated or untreated IgG from healthy controls (H) or patients with LN (a representative experiment is shown). (D) Densitometry was performed for quantification of the results in C (3 independent experiments were performed). Data are shown as mean ± SEM. ***P < 0.01, by 1-way ANOVA with Bonferroni post hoc test correction. (E) CaMK4 expression in podocytes after exposure to IgG derived from a patient with LN before (noRx) or after treatment with β-N-acetylglucosaminidase (AC), Neuraminidase A (NA), Neuraminidase S (NS), or α-fucosidase (F). (F) Densitometry was performed for quantification of the results in E. Data are shown as mean ± SEM. *P < 0.05; ***P < 0.01, by 1-way ANOVA with Bonferroni post hoc test correction (3 independent experiments utilizing IgG from 3 different individuals were performed for each representative experiment displayed above). (G) CaMK4 expression was evaluated after exposure of podocytes to IgG differing in glycosylation profiles from individuals with LN in remission, those with SLE with and without nephritis, and those without disease.