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Essential role and therapeutic targeting of the glomerular endothelial glycocalyx in lupus nephritis
Hiroyuki Kadoya, … , Chaim O. Jacob, János Peti-Peterdi
Hiroyuki Kadoya, … , Chaim O. Jacob, János Peti-Peterdi
Published September 1, 2020
Citation Information: JCI Insight. 2020;5(19):e131252. https://doi.org/10.1172/jci.insight.131252.
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Research Article Nephrology

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

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Abstract

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.

Authors

Hiroyuki Kadoya, Ning Yu, Ina Maria Schiessl, Anne Riquier-Brison, Georgina Gyarmati, Dorinne Desposito, Kengo Kidokoro, Matthew J. Butler, Chaim O. Jacob, János Peti-Peterdi

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Figure 6

Quantitative evaluation of the specific HA content of the glomerular endothelial glycocalyx in various mouse models.

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Quantitative evaluation of the specific HA content of the glomerular end...
(A–D) Representative images of Alexa Fluor 594–conjugated HABP (red) labeling of fixed kidney sections. (E and F) Summary and statistical analysis of percentage area of HABP labeling (E) and HABP fluorescence intensity (F) in n = 6 glomeruli from n = 3 mice in each group. Scale bar: 50 μm. Values are expressed as means ± SEM. *P < 0.0001, based on 1-way ANOVA followed by Tukey’s multiple-comparisons test (E and F). G, glomeruli; H, hyaluronidase; STZ, streptozotocin-induced diabetic mice.

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