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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 3

Evaluation of the phenotype of NZM.BAFFTg mice by MPM imaging and cytometry.

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Evaluation of the phenotype of NZM.BAFFTg mice by MPM imaging and cytome...
Intravascular space (plasma) was labeled with intravenous-injected (iv-injected) albumin–Alexa Fluor 594 (red). (A–D) Representative images of glomeruli in C57BL/6, NZM WT (4–6 weeks and 7–9 months), and NZM.BAFFTg (4–6 weeks) mice. Scale bar: 50 μm. Summary of (E) glomerular diameter evaluating hypertrophy (n = 8–48 glomeruli from n = 4 mice each group) and (F) glomerular sieving coefficient (GSC) evaluating albumin leakage into Bowman’s space (n = 8–10 glomeruli from n = 4 mice each group). (G) Quantification of activated memory T cells (presented as % of CD3+) in the tubulointerstitial (Tub-int) and glomerular (Glom) kidney compartments and spleen. Data are expressed as means ± SEM. *P < 0.05, **P < 0.01 using 1-way ANOVA followed by Tukey’s multiple-comparisons test (E and F).

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