Abstract: FR-PO273
Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells
Session Information
- Diabetic Kidney Disease: Basic - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Author
- El-Osta, Sam, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
Background
Hyperglycemia influences the development of glomerular endothelial cell damage, and nowhere is this more evident than in the progression of diabetic kidney disease (DKD). While the Set7 lysine methyltransferase is a known hyperglycemic sensor, its role in endothelial cell function in the context of DKD remains poorly understood.
Methods
Single-cell transcriptomics was used to investigate Set7 regulation in a mouse model of DKD, followed by validation of findings using pharmacological and short hairpin RNA inhibition inhibition of Set7.
Results
Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single-cell RNA-sequencing data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of glomerular endothelial cell populations by transcriptional regulation of the insulin growth factor binding protein 5 (IGFBP5). Chromatin immunoprecipitation assays confirmed that the expression of the IGFBP5 gene was associated with mono- and dimethylation of histone H3 lysine 4 (H3K4me1/2). This generalizability was investigated in human kidney and circulating hyperglycemic cells exposed to TGFβ1. We showed that the highly selective Set7 inhibitor (R)-PFI-2 hydrochloride attenuated indices associated with renal cell damage and mesenchymal transition, specifically (1) reactive oxygen species production, (2) IGFBP5 gene regulation, and (3) expression of mesenchymal markers. Furthermore, renal benefit observed in Set7KO diabetic mice closely corresponded in human glomerular endothelial cells with (R)-PFI-2 hydrochloride inhibition or Set7 short hairpin RNA silencing.
Conclusion
Set7 regulates the phenotypic endothelial–mesenchymal transition switch and suggests that targeting the lysine methyltransferase could protect glomerular cell injury in DKD.