Document Type

Article

Publication Date

3-2026

Identifier

DOI: 10.1016/j.xkme.2025.101235; PMCID: PMC12882720

Abstract

RATIONALE & OBJECTIVE: Idiopathic nephrotic syndrome (INS) is viewed as a podocyte-specific disease. Recent reports indicate endothelial involvement, but its significance is unclear. Here, we investigated the relationship between the glomerular expression of selected genes relevant to endothelial health and clinical markers of disease severity.

STUDY DESIGN: A cross-sectional study.

SETTING & PARTICIPANTS: Patients with INS (n = 70 minimal change disease and n = 83 focal segmental glomerulosclerosis) from the Nephrotic Syndrome Study Network cohort study and 53 control participants. Validation studies, including animal and cell culture experiments, were performed.

EXPOSURE: Gene expression analysis from micro-dissected human glomeruli. The study is focused on 10 genes highly relevant for endothelial homeostasis and barrier integrity (nitric oxide synthase 3 [NOS3], endothelial cell adhesion molecule, and endothelial cell specific molecule 1 [ESM1]), endothelial glycocalyx remodeling (HPSE, HYAL1, MMP2, MMP9, and ADAMTS1), and endothelial activation (ICAM1 and CAV1).

OUTCOMES: Kidney function, ultrastructural changes in podocytes and glomerular endothelium, interstitial fibrosis and tubular atrophy.

ANALYTICAL APPROACH: One-way ANOVA and Tukey's multiple comparisons test, Pearson Correlation and Cohen's d statistics.

RESULTS: Transcriptomic analysis revealed that all genes of interest were highly expressed in glomeruli from INS patients compared with controls, except for ESM1 and MMP9, which were decreased. Expression of endothelial-specific genes correlated with those of glycocalyx injury and cell activation. HPSE, ADAMTS1, ICAM1, and CAV1 expression was inversely associated with kidney function, whereas ADAMTS1 showed a positive association with proteinuria. NOS3, HPSE, and ADAMTS1 were associated with podocyte foot process effacement, and ICAM1 with podocyte detachment. HPSE and MMP2 were associated with ultrastructural endothelial injury, whereas HPSE, MMP2, ICAM1, and CAV1 were associated with interstitial fibrosis and tubular atrophy. Several genes (ESM1, HPSE, HYAL1, MMP2, and ICAM1) were also dysregulated in experimental INS and validated in cultured glomerular endothelial cells (NOS3 and heparanase) following exposure to INS sera.

LIMITATIONS: Observational study, selection bias, unmeasured confounders.

CONCLUSIONS: INS involves dysregulation of genes relevant for endothelial health.

Journal Title

Kidney Med

Volume

8

Issue

3

First Page

101235

Last Page

101235

PubMed ID

41659822

Keywords

Glomerular disease; NEPTUNE; glomerular endothelial cell; idiopathic nephrotic syndrome; transcriptomics

Comments

Grants and funding

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://www.kidneymedicinejournal.org/article/S2590-0595(25)00271-7/fulltext

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