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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 1

Accumulation of activated memory T cells in spleens correlate with LN disease progression in NZM.2328 mice.

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Accumulation of activated memory T cells in spleens correlate with LN di...
(A) Activated memory T cells were enumerated by flow cytometry from splenocytes purified from the different mouse lines at the ages indicated. Data are presented as box plots, where the boxes represent the 25th to 75th percentiles, the lines within the boxes represent the median, and the lines outside the boxes the 10th and 90th percentiles. Each circle represents an individual mouse. (B) Assessment of renal pathology in the different lines of mice. Data are presented as total kidney histology scores (KHSs) in the NZM.2328 mice with the indicated genotypes at the indicated ages. Each symbol represents an individual mouse. Results are plotted as in A. (C) Naive and activated memory T cells were stimulated with PMA and ionomycin for 5 hours and Brefeldin A (BFA) for 4 hours (day 0) or were stimulated with anti-CD3/CD28–coated beads for 5 days,and PMA + ionomycin were added to the culture for the last 5 hours as above and stained for intracellular IL-17A at day 0 and day 5. (D) Comparison between IL-17A production by activated memory T cells from age-matched NZM and C57BL/6 female mice stimulated as above. (E) IL-17A levels measured by commercial ELISA in supernatants from cultures of activated T cells isolated and stimulated as above. (C and D) Representative flow cytometry dot plots of 4 independent experiments are shown. (D and E) n = 5 per each group. (A–E) Only statistically significant differences are marked, based on using 1-way ANOVA followed by Tukey’s multiple-comparisons test (A and B) and unpaired Student’s t test (E). *P < 0.01, **P < 0.001, ***P < 0.0001.

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