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

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 7

Fluorescence labeling and in vivo MPM imaging of endogenous CD3+CD44+ T cells and the effects of H treatment (0–50 U iv) in the same glomeruli of NZM.BAFFTg mice.

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Fluorescence labeling and in vivo MPM imaging of endogenous CD3+CD44+ T ...
Intravascular space (plasma) was labeled with iv-injected albumin–Alexa Fluor 594 (red). (A–E) Representative images of endogenous T cells (arrows) labeled with iv-injected Alexa Fluor 488–conjugated anti-CD44 (green) and Alexa Fluor 594–conjugated anti-CD3 mAb (red) before and after H injection. All scale bars are 50 μm. We have confirmed that practically all CD44+ cells in glomeruli were also CD3+ (Supplemental Figure 4). (F–J) Representative images of albumin leakage into Bowman’s space (asterisk). (K) Dose-response curve of H effect on reducing the number of homed T cells in glomeruli and (L) Bowman’s space albumin fluorescence intensity indicating glomerular albumin leakage (n = 5 glomeruli from n = 3 mice each). (M–Q) Effects of H treatment (3 times 200 U each iv every other day) in NZM.BAFFTg mice. Representative images (M–O) of the same glomerulus before H treatment (day 0) and after the second (day 3) and third H injections (day 5). (P) Control time course and the effects of H or heparinase III treatment on albuminuria (urinary albumin/creatinine ratio, ACR) in NZM WT and NZM BAFFTg mice followed for 3 months. Values are expressed as means ± SEM, n = 6 mice each. *P < 0.001. (Q) Kaplan-Meier animal survival curve. *P < 0.001 BAFFTg vs. treatment; ns, not significant H vs. heparinase III treatment. One-way ANOVA followed by Tukey’s multiple-comparisons test was used (L–Q).