Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells
Scott Maxwell, Jun Okabe, Harikrishnan Kaipananickal, Hanah Rodriguez, Ishant Khurana, Keith Al-Hasani, Bryna S.M. Chow, Eleni Pitsillou, Tom C. Karagiannis, Karin Jandeleit-Dahm, Ronald C.W. Ma, Yu Huang, Juliana C.N. Chan, Mark E Cooper, Assam El-Osta- Nephrology
- General Medicine
Background
Hyperglycaemia 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 hyperglycaemic 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 shRNA inhibition of Set7.
Results
Set7 knockout (Set7KO) improved glomerular structure and albuminuria in a mouse model of diabetes. Analysis of single cell RNA-seq (scRNA-seq) data showed dynamic transcriptional changes in diabetic renal cells. Set7KO controls phenotype switching of GEN cell populations through transcriptional regulation of IGFBP5 (Insulin growth factor binding protein 5). Chromatin immunoprecipitation assays confirmed the expression of the
Conclusions
Set7 regulates the phenotypic endothelial-mesenchymal transition (EDMT) switch and suggest that targeting the lysine methyltransferase could protect glomerular cell injury in DKD.