Roles of glomerular endothelial hyaluronan in the development of proteinuria.
Animals
Cattle
Endothelial Cells
/ drug effects
Female
Glycocalyx
/ drug effects
Humans
Hyaluronic Acid
/ biosynthesis
Hyaluronoglucosaminidase
/ administration & dosage
Kidney Glomerulus
/ drug effects
Male
Mice
Mice, Inbred C57BL
Organ Culture Techniques
Pregnancy
Proteinuria
/ metabolism
Rats
Rats, Inbred Lew
anti-VEGF therapy
glycocalyx
hyaluronan
isolated perfused kidney
proteinuria
Journal
Physiological reports
ISSN: 2051-817X
Titre abrégé: Physiol Rep
Pays: United States
ID NLM: 101607800
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
01
08
2021
received:
01
08
2021
accepted:
04
08
2021
entrez:
2
9
2021
pubmed:
3
9
2021
medline:
25
2
2022
Statut:
ppublish
Résumé
Vascular endothelial cells are covered with glycocalyx comprising heparan sulfate, hyaluronan, chondroitin sulfate, and associated proteins. Glomerular endothelial glycocalyx is involved in protecting against induction of proteinuria and structural damage, but the specific components in glycocalyx that represent therapeutic targets remain unclear. Anti-vascular endothelial growth factor (VEGF) therapy is associated with an increased risk of glomerular endothelial injury. This study investigated whether hyaluronan could provide a therapeutic target to protect against proteinuria. We conducted ex vivo and in vivo experiments to explore the effects of degrading glomerular hyaluronan by administering hyaluronidase and of supplementation with hyaluronan. We investigated hyaluronan expression using biotin-labeled hyaluronan-binding protein (HABP) in human kidney specimens or serum hyaluronan in endothelial injuries under inhibition of VEGF signaling. We directly demonstrated hyaluronan in glomerular endothelial layers using HABP staining. Ex vivo and in vivo experiments showed the development of proteinuria after digestion of hyaluronan in glomerular capillaries. Supplementation with hyaluronan after hyaluronidase treatment suppressed proteinuria. Mice in the in vivo study developed albuminuria after intraperitoneal injection of hyaluronidase with decreased glomerular hyaluronan and increased serum hyaluronan. In human kidneys with endothelial cell dysfunction and proteinuria due to inhibition of VEGF, glomerular expression of hyaluronan was reduced even in normal-appearing glomeruli. Serum hyaluronan levels were elevated in patients with pre-eclampsia with VEGF signaling inhibition. Our data suggest that hyaluronan itself plays crucial roles in preventing proteinuria and preserving the integrity of endothelial cells. Hyaluronan could provide a therapeutic target for preventing glomerular endothelial glycocalyx damage, including VEGF signaling inhibition.
Identifiants
pubmed: 34472715
doi: 10.14814/phy2.15019
pmc: PMC8411502
doi:
Substances chimiques
Hyaluronic Acid
9004-61-9
Hyaluronoglucosaminidase
EC 3.2.1.35
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e15019Informations de copyright
© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
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