Essential role and therapeutic targeting of the glomerular endothelial glycocalyx in lupus nephritis

Lupus nephritis (LN) is a major organ complication and cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is an unmet medical need for developing more efficient and specific, mechanism-based therapies, which depends on improved understanding of the underlying...

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Bibliographic Details
Published in:JCI insight 2020-10, Vol.5 (19)
Main Authors: Kadoya, Hiroyuki, Yu, Ning, Schiessl, Ina Maria, Riquier-Brison, Anne, Gyarmati, Georgina, Desposito, Dorinne, Kidokoro, Kengo, Butler, Matthew J, Jacob, Chaim O, Peti-Peterdi, János
Format: Article
Language:English
Subjects:
Animals
Endothelium, Vascular - immunology
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Female
Glycocalyx - metabolism
Hyaluronic Acid - metabolism
Hyaluronoglucosaminidase - administration & dosage
Immunologic Memory - immunology
Kidney Glomerulus - immunology
Kidney Glomerulus - metabolism
Kidney Glomerulus - pathology
Lupus Nephritis - immunology
Lupus Nephritis - metabolism
Lupus Nephritis - pathology
Lupus Nephritis - prevention & control
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nephrology
Polysaccharide-Lyases - administration & dosage
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
T-Lymphocytes - pathology
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Summary:Lupus nephritis (LN) is a major organ complication and cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is an unmet medical need for developing more efficient and specific, mechanism-based therapies, which depends on improved understanding of the underlying LN pathogenesis. Here we present direct visual evidence from high-power intravital imaging of the local kidney tissue microenvironment in mouse models showing that activated memory T cells originated in immune organs and the LN-specific robust accumulation of the glomerular endothelial glycocalyx played central roles in LN development. The glomerular homing of T cells was mediated via the direct binding of their CD44 to the hyaluronic acid (HA) component of the endothelial glycocalyx, and glycocalyx-degrading enzymes efficiently disrupted homing. Short-course treatment with either hyaluronidase or heparinase III provided long-term organ protection as evidenced by vastly improved albuminuria and survival rate. This glycocalyx/HA/memory T cell interaction is present in multiple SLE-affected organs and may be therapeutically targeted for SLE complications, including LN.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.131252