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

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

doi:10.1172/jci.insight.147789

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

Rhea Bhargava,¹ Sylvain Lehoux,² Kayaho Maeda,¹ Maria G. Tsokos,¹ Suzanne Krishfield,¹ Lena Y. Ellezian,¹ Martin Pollak,¹ Isaac E. Stillman,³ Richard D. Cummings,² and George C. Tsokos¹

Published March 30, 2021 - More info

View PDF

Abstract

Lupus nephritis (LN) is a serious complication occurring in 50% of patients with systemic lupus erythematosus (SLE) for which there is lack of biomarkers, specific medications, and 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 NFκB, 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 new 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.

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

Rhea Bhargava,¹ Sylvain Lehoux,² Kayaho Maeda,¹ Maria G. Tsokos,¹ Suzanne Krishfield,¹ Lena Y. Ellezian,¹ Martin Pollak,¹ Isaac E. Stillman,³ Richard D. Cummings,² and George C. Tsokos¹

Article tools

Metrics

Go to

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

Rhea Bhargava,1 Sylvain Lehoux,2 Kayaho Maeda,1 Maria G. Tsokos,1 Suzanne Krishfield,1 Lena Y. Ellezian,1 Martin Pollak,1 Isaac E. Stillman,3 Richard D. Cummings,2 and George C. Tsokos1

Article tools

Metrics

Go to

Sign up for email alerts

Rhea Bhargava,¹ Sylvain Lehoux,² Kayaho Maeda,¹ Maria G. Tsokos,¹ Suzanne Krishfield,¹ Lena Y. Ellezian,¹ Martin Pollak,¹ Isaac E. Stillman,³ Richard D. Cummings,² and George C. Tsokos¹