Minimal Change Disease Is Associated With Endothelial Glycocalyx Degradation and Endothelial Activation

Colin Bauer; Federica Piani; Mindy Banks; Flor A Ordoñez; Carmen de Lucas-Collantes; Kaori Oshima; Eric P Schmidt; Igor Zakharevich; Alfons Segarra; Cristina Martinez; Carlos Roncal-Jimenez; Simon C Satchell; Petter Bjornstad; Marshall Scott Lucia; Judith Blaine; Joshua M Thurman; Richard J Johnson; Gabriel Cara-Fuentes

doi:10.1016/j.ekir.2021.11.037

Minimal Change Disease Is Associated With Endothelial Glycocalyx Degradation and Endothelial Activation

Kidney Int Rep. 2021 Dec 16;7(4):797-809. doi: 10.1016/j.ekir.2021.11.037. eCollection 2022 Apr.

Authors

Colin Bauer¹, Federica Piani^{1

2}, Mindy Banks³, Flor A Ordoñez⁴, Carmen de Lucas-Collantes⁵, Kaori Oshima⁶, Eric P Schmidt⁶, Igor Zakharevich⁶, Alfons Segarra^{7

8

9}, Cristina Martinez⁸, Carlos Roncal-Jimenez¹⁰, Simon C Satchell¹¹, Petter Bjornstad^{10

12}, Marshall Scott Lucia¹³, Judith Blaine¹⁰, Joshua M Thurman¹⁰, Richard J Johnson¹⁰, Gabriel Cara-Fuentes^{1

10}

Affiliations

¹ Section of Pediatric Nephrology, Department of Pediatrics, Children's Hospital Colorado, Aurora, Colorado, USA.
² Department of Medicine and Surgery Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.
³ Division of Pediatric Nephrology, Rocky Mountain Children's Hospital, Denver, Colorado, USA.
⁴ Division of Pediatric Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain.
⁵ Division of Pediatric Nephrology, Hospital Niño Jesus, Madrid, Spain.
⁶ Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
⁷ Department of Nephrology, Hospital Universitario Arnau de Vilanova, Lleida, Spain.
⁸ Lleida Institute for Biomedical Research Dr. Pifarré Foundation, Lleida, Spain.
⁹ Division of Nephrology, Hospital General Vall d'Hebron, Barcelona, Spain.
¹⁰ Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹¹ Bristol Renal, University of Bristol, Bristol, UK.
¹² Department of Pediatrics, Section of Pediatric Endocrinology, Children's Hospital Colorado and University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
¹³ Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Abstract

Introduction: Minimal change disease (MCD) is considered a podocyte disorder triggered by unknown circulating factors. Here, we hypothesized that the endothelial cell (EC) is also involved in MCD.

Methods: We studied 45 children with idiopathic nephrotic syndrome (44 had steroid sensitive nephrotic syndrome [SSNS], and 12 had biopsy-proven MCD), 21 adults with MCD, and 38 healthy controls (30 children, 8 adults). In circulation, we measured products of endothelial glycocalyx (EG) degradation (syndecan-1, heparan sulfate [HS] fragments), HS proteoglycan cleaving enzymes (matrix metalloprotease-2 [MMP-2], heparanase activity), and markers of endothelial activation (von Willebrand factor [vWF], thrombomodulin) by enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. In human kidney tissue, we assessed glomerular EC (GEnC) activation by immunofluorescence of caveolin-1 (n = 11 MCD, n = 5 controls). In vitro, we cultured immortalized human GEnC with sera from control subjects and patients with MCD/SSNS sera in relapse (n = 5 per group) and performed Western blotting of thrombomodulin of cell lysates as surrogate marker of endothelial activation.

Results: In circulation, median concentrations of all endothelial markers were higher in patients with active disease compared with controls and remained high in some patients during remission. In the MCD glomerulus, caveolin-1 expression was higher, in an endothelial-specific pattern, compared with controls. In cultured human GEnC, sera from children with MCD/SSNS in relapse increased thrombomodulin expression compared with control sera.

Conclusion: Our data show that alterations involving the systemic and glomerular endothelium are nearly universal in patients with MCD and SSNS, and that GEnC can be directly activated by circulating factors present in the MCD/SSNS sera during relapse.

Keywords: endothelial activation; endothelial glycocalyx; glomerular endothelial cell; minimal change disease; podocyte; steroid sensitive nephrotic syndrome.

Abstract

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