Key result
Impdh1 silencing reduces endothelial damage and inhibits aortic pyroptosis in diabetic angiopathy models.
Why the study?
The mechanisms by which pyroptosis contributes to diabetic angiopathy have not been fully elucidated.
Does silencing Impdh1 prevent endothelial cell pyroptosis and damage in models of diabetic angiopathy?
Does silencing Impdh1 prevent endothelial cell pyroptosis and damage in models of diabetic angiopathy?
Impdh1 is a key protein promoting diabetic vasculopathy, and its silencing protects aortic endothelial cells by inhibiting pyroptosis and inflammation.
Preclinical mouse data warrant caution before any clinical use; hypothesis-generating for Impdh1-targeted therapies in diabetic vasculopathy.
BACKGROUND: Diabetic angiopathy (DA) is a diabetic vascular complication. Pyroptosis is an inflammatory death that plays an important role in the development of DA, but the underlying mechanisms have not been fully elucidated. METHODS: The GSE169332 dataset from the Gene Expression Omnibus (GEO) was subjected to single-cell RNA sequencing (scRNA-seq) analysis, and the data of diabetic mice were subjected to bulk RNA-seq. The pathway through which the inflammatory microenvironment participated in the DA was explored by pseudotime analysis and cell-cell communication. DA models were constructed using in vitro mouse models. The histopathological changes in the collected aorta were observed by hematoxylin and eosin (H&E) and Masson staining. The distribution and expression of the phenotypic markers related to pyroptosis in aortic tissues (NLRP3, pro-Caspase1, and GSDMD-N) were observed by immunohistochemistry (IHC) or immunofluorescence (IF) staining. Following the silencing of the expression of high glucose (HG)-induced Impdh1 in endothelial cells (ECs), Impdh1 expression was detected by real-time quantitative reverse transcription PCR (qRT-PCR), and the expression of Impdh1, NLRP3, pro-Caspase1, and GSDMD was detected by IF staining; cell migration was detected by cell scratch assay, cell viability was detected by cell counting kit-8 (CCK-8) assay, and tube formation was detected by tube formation assay; the levels of IL-1β and IL-18 were detected using the enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Impdh1 was identified by scRNA-seq and bulk RNA-seq as a key molecule in the progression of DA associated with pyroptosis of aortic ECs. By constructing mouse models of DA, it was found that silencing Impdh1 can inhibit mouse aortic pyroptosis. Silencing of the expression of HG-induced Impdh1 revealed an effective amelioration of EC damage and pyroptosis. CONCLUSION: Impdh1 is identified as a potential pyroptosis-related gene associated with DA by scRNA-seq of GEO data and bulk RNA-seq. Impdh1 protects aortic ECs by inhibiting pyroptosis and inflammation. CLINICAL TRIAL NUMBER: Not applicable.
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Xie et al. (2025) studied Diabetic angiopathy. Impdh1 silencing vs. Control was evaluated on Aortic pyroptosis and endothelial cell damage. Silencing Impdh1 ameliorated endothelial cell damage and inhibited aortic pyroptosis in mouse models of diabetic angiopathy.
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