Perturbations in podocyte transcriptome and biological pathways induced by FSGS associated circulating factors.
CD40
autoantibody
focal segmental glomerulosclerosis (FSGS)
kidney transplantation
soluble urokinase-type plasminogen activator receptor (suPAR)
Journal
Annals of translational medicine
ISSN: 2305-5839
Titre abrégé: Ann Transl Med
Pays: China
ID NLM: 101617978
Informations de publication
Date de publication:
30 Jun 2023
30 Jun 2023
Historique:
received:
13
08
2022
accepted:
03
12
2022
medline:
5
7
2023
pubmed:
5
7
2023
entrez:
5
7
2023
Statut:
ppublish
Résumé
Focal segmental glomerulosclerosis (FSGS) is frequently associated with heavy proteinuria and progressive renal failure requiring dialysis or kidney transplantation. However, primary FSGS also has a ~40% risk of recurrence of disease in the transplanted kidney (rFSGS). Multiple circulating factors have been identified to contribute to the pathogenesis of primary and rFSGS including soluble urokinase-type plasminogen activator receptor (suPAR) and patient-derived CD40 autoantibody (CD40autoAb). However, the downstream effector pathways specific to individual factors require further study. The tumor necrosis factor, TNF pathway activation by one or more circulating factors present in the sera of patients with FSGS has been supported by multiple studies. A human Here we show that podocyte injury caused by sera from FSGS patients is mediated by CD40 and suPAR and can be blocked by human anti-uPAR and anti-CD40 antibodies. Transcriptomic studies to compare the molecules and pathways activated in response to CD40 autoantibody from rFSGS patients (rFSGS/CD40autoAb) and suPAR, identified unique inflammatory pathways associated with FSGS injury. We identified several novel and previously described genes associated with FSGS progression. Targeted blockade of suPAR and CD40 pathways with novel human antibodies showed inhibition of podocyte injury in FSGS.
Sections du résumé
Background
UNASSIGNED
Focal segmental glomerulosclerosis (FSGS) is frequently associated with heavy proteinuria and progressive renal failure requiring dialysis or kidney transplantation. However, primary FSGS also has a ~40% risk of recurrence of disease in the transplanted kidney (rFSGS). Multiple circulating factors have been identified to contribute to the pathogenesis of primary and rFSGS including soluble urokinase-type plasminogen activator receptor (suPAR) and patient-derived CD40 autoantibody (CD40autoAb). However, the downstream effector pathways specific to individual factors require further study. The tumor necrosis factor, TNF pathway activation by one or more circulating factors present in the sera of patients with FSGS has been supported by multiple studies.
Methods
UNASSIGNED
A human
Results
UNASSIGNED
Here we show that podocyte injury caused by sera from FSGS patients is mediated by CD40 and suPAR and can be blocked by human anti-uPAR and anti-CD40 antibodies. Transcriptomic studies to compare the molecules and pathways activated in response to CD40 autoantibody from rFSGS patients (rFSGS/CD40autoAb) and suPAR, identified unique inflammatory pathways associated with FSGS injury.
Conclusions
UNASSIGNED
We identified several novel and previously described genes associated with FSGS progression. Targeted blockade of suPAR and CD40 pathways with novel human antibodies showed inhibition of podocyte injury in FSGS.
Identifiants
pubmed: 37404982
doi: 10.21037/atm-22-3670
pii: atm-11-09-315
pmc: PMC10316099
doi:
Types de publication
Journal Article
Langues
eng
Pagination
315Informations de copyright
2023 Annals of Translational Medicine. All rights reserved.
Déclaration de conflit d'intérêts
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3670/coif). MMS is a founder of technology for the assessment of kidney injury, owned by the regents, University of California. As the founder she has financial or non-financial interests in Nephrosant. JR reports that he receives consulting fees from Reata, Novateur Ventures, Walden Biosciences, Biomarin, Astellas, Massachusetts General Hospital, Genentech, Up to Date, Merck, Insceptionsci, GL, Visterra, Aclipse and MantraBio. JR also has several patents: US20110212083-Role of soluble uPAR in the Pathogenesis of Proteinuric Kidney Disease, S9867923-Reducing Solucble Rokinase Receptor in the Circulation, JP2016530510-Non-Glycoslyated suPAR Biomarkers and Uses thereof, US20160296592-Methods/Compositions for the Treatment of Proteinuric Diseases, US9144594-Dynamin Mediated Diseases and US8809386-Dynamin Ring Stabilizers. JR is on Scientific advisory board of Walden Biosciences and has stocks/stock options at Walden Biosciences and Aclipse. The other authors have no conflicts of interest to declare.
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