Dataset Information

Functional targeting of PTTG1 in pericytes restores vascular integrity in diabetic retina

ABSTRACT:

Pericyte loss is an early and critical event in the pathogenesis of diabetic retinopathy (DR), yet the molecular mechanisms underlying pericyte dysfunction remain incompletely understood. Using single-cell RNA sequencing, we generated a retinal cellular overview comprising 18,926 cells from diabetic and non-diabetic mice. We identified a previously unrecognized pericyte subpopulation defined by high expression of pituitary tumor transforming gene 1 (PTTG1), which was enriched in diabetic retina. Functional studies demonstrated that CRISPR/Cas9 or siRNA-mediated silencing of PTTG1 restored pericyte stability and barrier-supporting function under high-glucose stress. In vivo, knockdown of PTTG1 via lentiviral or pericyte-specific AAV delivery improved retinal vascular integrity and reduced retinal vascular function in diabetic mice. Integrated transcriptomic and metabolomic profiling revealed PTTG1 knockdown reprogrammed metabolism by modulating glycolytic flux and attenuating oxidative stress. Furthermore, a therapeutic strategy employing spherical nucleic acid-based siPTTG1 nanocarriers (sTDN-siPTTG1) significantly ameliorated retinal vascular dysfunction in DR model. These findings suggest that PTTG1 is a critical regulator of pericyte metabolic homeostasis and microvascular function in DR, highlighting its translational potential as a therapeutic target for diabetic microvascular complications.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS13544 | MetaboLights | 2026-03-27

REPOSITORIES: MetaboLights

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	a_MTBLS13544_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13544_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13544_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13544_LC-MS_positive_hilic_metabolite_profiling_v2_maf.tsv	Tabular

Items per page:

1 - 5 of 6

Similar Datasets

Project description:Diabetic retinopathy (DR), the leading cause of blindness in working-age adults, is thought to be primarily a microvascular complication of diabetes. As a central element of the retinal neurovascular unit, Müller cells, the major macroglia of the retina, are important for maintaining a healthy and functional retina and play a critical role in several pathological events during DR disease progression. Here, we aim to improve our understanding of Müller cell-specific signalling pathways that are altered during DR disease progression in order to develop novel gene therapy strategies that target Müller cells. We used a multi-omics approach on purified Müller cells from 6-month-old control and diabetic db/db mice, including (i) RNA-seq followed by oPOSSUM-3 transcription factor (TF) binding site cluster analysis, (ii) glial chromatin landscape analysis by ATAC-seq, and (iii) Müller cell proteomics by MS/MS mass spectrometry. This led to the identification of the glucocorticoid receptor (GR, gene ID: Nr3c1) most highly expressed in Müller cells. In cells from diabetic mice, GR mRNA and protein expression is significantly reduced and its target gene cluster downregulated in Müller cells. Importantly, GR was identified as a potential master regulator not only by oPOSSUM analysis based on differentially expressed mRNA in Müller cells, but also validated by the ATAC-seq approach. In an in vitro cortisol-stimulated retinal explant model cortisol not only increased GR phosphorylation, but also induced changes in the expression of known downstream GR target genes. Finally, we evaluated whether AAV-mediated GR overexpression in Müller cells improves retinal functionality and we found moderate improvements indicated by electroretinography. While synthetic and topical glucocorticoids are widely used in ophthalmology with undeniable beneficial effects, our study provides valuable new insight into the role of GR signalling and glial alterations in the diabetic retina. This supports the therapeutic concept of locally enhancing the GR signaling axis. Our findings of reduced GR levels in Müller cells of the diabetic retina suggests that therapeutic approaches should aim at increasing the expression of the receptor rather than adding more ligand.

Dataset Information

Functional targeting of PTTG1 in pericytes restores vascular integrity in diabetic retina

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets