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

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

doi:10.1172/jci.insight.147789

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.

Highlights

Lupus nephritis (LN) represents one of the most serious complications of systemic lupus erythematosus (SLE) and is associated with significant morbidity and mortality
We found that CaMK4 expression at the protein and mRNA levels increased only in podocytes cultured in the presence of IgG from patients with active LN and not in podocytes exposed to IgG from healthy controls or SLE patients without LN (Figure 1, A–C)
We demonstrate that CaMK4 is overexpressed in podocytes of individuals with active LN and that IgG from patients with SLE without kidney involvement does not have the ability to upregulate CaMK4, whereas IgG isolated from individuals with LN can injure podocytes through the upregulation of CaMK4

Summary

Introduction

Lupus nephritis (LN) represents one of the most serious complications of systemic lupus erythematosus (SLE) and is associated with significant morbidity and mortality. The pathogenesis of LN involves the deposition of circulating or in situ–formed immune complexes in different areas of the glomerulus, leading to activation of components of the innate and adaptive immune system [12,13,14,15,16]. It has been proposed that podocyte injury occurs early in LN after deposition of immune complexes and precedes irreversible glomerular damage [17,18,19]. Depletion of more than 30% of podocytes causes glomerular destabilization, which leads to eventual glomerulosclerosis and has been associated with the severity of LN [20, 21]

Methods

Results

Conclusion