Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Nephrology

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

  • Text
  • PDF
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

×

Figure 4

In vivo MPM imaging of the glomerular homing of exogenous and endogenous activated memory T cells.

Options: View larger image (or click on image) Download as PowerPoint
In vivo MPM imaging of the glomerular homing of exogenous and endogenous...
Intravascular space (plasma) was labeled with iv injected albumin–Alexa Fluor 594 (red). Female 4- to 6-week-old NZM WT (A and B) and NZM.BAFFTg (C–E) mice were treated with l-NAME and high-salt diet (HS) (B) or vehicle (A and C) followed by iv injection of FACS-sorted splenic activated memory T cells (sAMTs) (A–C). All transferred activated memory T cells were obtained from 7- to 9-month-old NZM.2328 female mouse donors. (D) sAMTs were preincubated with HA before iv injection. (E) sAMTs were preincubated with anti-CD44 antibody (KM81) before iv injection. (F) Summary of the number of sAMTs homed in glomeruli of the different groups of mice (n = 9–13 glomeruli from n = 4 mice for A–D and n = 3 mice for E). (G–Q) Fluorescence labeling and MPM imaging of endogenous CD3+CD44+ T cells, in C57BL/6 (n = 3), NZM WT (n = 3), and NZM.BAFFTg (n = 10) mouse glomeruli (4–6 weeks old) and NZM WT (7–9 months, n = 1). (G, I, K, and M) Representative images at baseline before and (H, J, L, and N) after endogenous T cells labeled in same glomeruli. (O) Image of the same glomerulus as in N 1 hour after H injection. (P) Overview image of a large kidney surface area in a 4-week-old female NZM.BAFFTg mouse. Note the high density of endogenous T cells (green) in 3 glomeruli (G) compared with adjacent tubulointerstitial areas. (Q) Summary of the number of CD3+CD44+ T cells homed in glomeruli of different mouse groups at 4–6 weeks. (R) Normalized density of CD44+ cells homed to glomeruli after acute H injection, compared with baseline (dotted line at 100%). Scale bars: 50 μm. Values are expressed as means ± SEM, *P < 0.0001 based on using 1-way ANOVA followed by Tukey’s multiple-comparisons test (F–Q) and unpaired Student’s t test (R). Positive cells are depicted by white arrows. HA, hyaluronic acid; H, hyaluronidase.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts