Extracellular vesicles from focal segmental glomerulosclerosis pediatric patients induce STAT3 activation and mesangial cell proliferation

Naile T Pekkucuksen; Lauren P Liu; Rasha Aly; Lawrence R Shoemaker; Abdel A Alli

doi:10.1371/journal.pone.0274598

Extracellular vesicles from focal segmental glomerulosclerosis pediatric patients induce STAT3 activation and mesangial cell proliferation

PLoS One. 2022 Nov 14;17(11):e0274598. doi: 10.1371/journal.pone.0274598. eCollection 2022.

Authors

Naile T Pekkucuksen¹, Lauren P Liu², Rasha Aly¹, Lawrence R Shoemaker¹, Abdel A Alli^{1

2

3}

Affiliations

¹ Division Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America.
² Department of Physiology and Aging, University of Florida, Gainesville, Florida, United States of America.
³ Department of Medicine Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida, United States of America.

Abstract

Introduction: Primary focal segmental glomerulosclerosis (FSGS), a major cause of end-stage kidney disease (ESKD) in adolescents and young adults, is attributable to recognized genetic mutations in a minority of cases. For the majority with idiopathic primary FSGS, the cause of the disease is unknown. We hypothesize that extracellular vesicle (EVs), that carry information between podocytes and mesangial cells, may play a key role in disease progression.

Material & methods: A total of 30 participants (20 primary nephrotic syndrome/ 10 healthy controls) were enrolled in this study. Primary nephrotic syndrome subjects were grouped based on pathologic diagnosis. The FSGS group was compared to healthy control subjects based on demographic and clinical findings. EVs were isolated from the urine of each group before being characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis. The effects of the EVs from each group on normal human mesangial cells and activation of certain pathways were then investigated.

Results: Based on demographic and clinical findings, mean serum creatinine was significantly higher in the FSGS group than the normal healthy control group. The mean size of the EVs in the FSGS group was significantly higher than the healthy control group. The mesangial cells that were challenged with EVs isolated from FSGS patients showed significant upregulation of STAT-3, PCNA, Ki67, and cell proliferation.

Discussion: Our data demonstrate that EVs from FSGS patients stimulate mesangial cell proliferation in association with upregulation of the phospho-STAT-3 pathway. Additional studies are planned to identify the molecular cargo within the EVs from FSGS patients that contribute to the pathogenesis of FSGS.

Copyright: © 2022 Pekkucuksen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Cell Proliferation
Child
Extracellular Vesicles* / metabolism
Glomerulosclerosis, Focal Segmental* / pathology
Humans
Nephrotic Syndrome* / pathology
Podocytes* / metabolism
STAT3 Transcription Factor / metabolism

Substances

STAT3 protein, human
STAT3 Transcription Factor

Grants and funding

This study was financially supported by the University of Florida College of Medicine in the form of start-up funds to AA. No additional external funding was received for this study.