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NDUFV1 Activation Mediates High Glucose-Induced Apoptosis in Peritoneal Mesothelial Cells

ABSTRACT: To elucidate the mechanisms underlying high glucose-induced Peritoneal mesothelial cells (PMCs) apoptosis, we obtained the first dynamic proteomic atlas of HMrSV5 cells under different concentration of glucose and mannitol stimulation. After excluding osmosis, 626 differentially expressed proteins (DEPs) were detected following high glucose stimulation. Notably, the up-regulated DEPs were significantly enriched in the oxidative phosphorylation pathway, implicating mitochondrial dysfunction in the apoptotic process. Protein-protein interaction network analysis further revealed that NDUFV1, a core subunit of mitochondrial Complex I, might be a key regulator. To validate clinical relevance, we performed a comparative proteomic analysis of peritoneal dialysis (PD) effluents from new and long-term PD patients. The clinical proteomics data revealed a marked enrichment of oxidative phosphorylation in the early-stage of dialysis patients, coinciding with notably up-regulation of NDUFV1. Molecular biology experiments demonstrated that the up-regulation of NDUFV1 increased reactive oxygen species production, disrupted mitochondrial membrane potential, thereby promoting apoptosis.

ORGANISM(S): Homo Sapiens

SUBMITTER: Chen Li

PROVIDER: PXD075115 | iProX | Tue Mar 03 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Expression data from peritoneal biopsies of patients with encapsulating peritoneal sclerosis (EPS), patients undergoing first implantation of a peritoneal dialysis catheter (PD), and patients undergoing abdominal surgery for non-peritoneal conditions (controls) We used microarrays to determine the transcriptional profiles of peritoneal membrane in patients with encapsulating peritoneal sclerosis (EPS), patients undergoing first insertion of a peritoneal dialysis cathetier (PD), and uremic patients without history of PD or EPS, undergoing abdominal surgery for non-peritoneal problems (CON) Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD), characterized by marked inflammation and severe fibrosis of the peritoneum, and associated with high morbidity and mortality. EPS can occur years after termination of PD and, in severe cases, leads to intestinal obstruction and ileus requiring surgical intervention. Despite ongoing research, the pathogenesis of EPS remains unclear. We performed a global transcriptome analysis of peritoneal tissue specimens from EPS patients, PD patients without EPS, and uremic patients without history of PD or EPS (Uremic). Unsupervised and supervised bioinformatics analysis revealed distinct transcriptional patterns that discriminated these three clinical groups. The analysis identified a signature of 219 genes expressed differentially in EPS as compared to PD and Uremic groups. Canonical pathway analysis of differentially expressed genes showed enrichment in several pathways, including antigen presentation, dendritic cell maturation, B cell development, chemokine signaling and humoral and cellular immunity (P value <0.05). Further interactive network analysis depicted effects of EPS-associated genes on networks linked to inflammation, immunological response, and cell proliferation. Gene expression changes were confirmed by qRT-PCR for a subset of the differentially expressed genes. EPS patient tissues exhibited elevated expression of genes encoding sulfatase1, thrombospondin 1, fibronectin 1 and alpha smooth muscle actin, among many others, while in EPS and PD tissues mRNAs encoding leptin and retinol-binding protein 4 were markedly down-regulated, compared to Uremic group patients. Immunolocalization of Collagen 1 alpha 1 revealed that Col1a1 protein was predominantly expressed in the submesothelial compact zone of EPS patient peritoneal samples, whereas PD patient peritoneal samples exhibited homogenous Col1a1 staining throughout the tissue samples. The results are compatible with the hypothesis that encapsulating peritoneal sclerosis is a distinct pathological process from the simple peritoneal fibrosis that accompanies all PD treatment. Total RNA was isolated from frozen peritoneal biopsy specimens obtained at time of surgery. RNA was hybridized to Affymetrix arrays, and analyzed. Select transcripts were subjected to validation by rt-pcr and by immunodetection.

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NDUFV1 Activation Mediates High Glucose-Induced Apoptosis in Peritoneal Mesothelial Cells

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