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

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.

Dapagliflozin Treatment Augments Bioactive Phosphatidylethanolamine Concentrations in Kidney Cortex Membrane Fractions of Hypertensive Diabetic db/db Mice and Alters the Density of Lipid Rafts in Mouse Proximal Tubule Cells

“…They are more than just waste-exporting vesicles, as they enable the transfer of mRNAs, microRNAs, DNA, and proteins across cells [ 22 ]. EVs have been shown to allow for intercellular communication within the nephron [ 23 ] and play a role in signal transduction [ 24 , 25 , 26 , 27 ]. EVs are a rich source of biomarkers, and recent research has shown that they may play a role in the pathophysiology of hypertension [ 21 ].…”

Urinary Extracellular Vesicles in Chronic Kidney Disease: From Bench to Bedside?

“…EVs from the FSGS group activated the signal transducer and activator of the transcription 3 (STAT3) pathway, which presumably leads to a dose-dependent increase in mesangial cell proliferation. When mesangial cells were challenged with EVs isolated from FSGS patients, proliferating cell nuclear antigen (PCNA), Ki67, and cell proliferation were also significantly increased [10].…”

“…The specific composition and function of EVs, which contain a subset of common proteins involved in biogenesis and trafficking, as well as a signature from the cell or tissue of origin, are explained by their different subcellular origin [6,9]. Because EV release and uptake are both dynamic processes regulated by a variety of mechanisms, it is difficult to accurately estimate the duration and concentration of EVs that a specific cell type would be exposed to in a physiological or pathophysiological scenario [10]. EVs modulate leukocyte adhesion, differentiation, and vascular function in inflammation, according to mechanistic data, and these studies have greatly improved our understanding of these pathophysiologic processes [11,12].…”

The View of Pediatric Nephrotic Syndrome as a Podocytopathy

“…In that sense, Eroglu et al (2021) have found that patients with SSNS during relapse had higher protein content in circulating plasma EVs, especially proteins that involved actin cytoskeleton rearrangement, such as Rasrelated C3 botulinum toxin substrate 1 (RAC-1) [242]. EVs have also been shown to induce mesangial cell proliferation in pediatric patients with FSGS through the phospho-STAT-3 pathway [243]. This topic has been recently reviewed elsewhere [244].…”