Advanced Glycation End Products Mediate Epigenetic Alteration of H3K27me3 in Renal Proximal Tubular Cells: Potential Role in Metabolic Memory
Year: 2025
Type: article
Abstract: The accumulation of advanced glycation end products (AGEs) is a hallmark of prolonged high glucose levels in diabetes mellitus. We have previously reported that hypoxia and AGEs cause epigenetic modification of the repressive mark H3K27me3 in podocytes by downregulation of enhancer of zeste homolog 2 (EZH2) and nuclear inhibitor of protein phosphatase 1 (NIPP1). However, their impact on proximal tubular cells remains unclear. The aim of this study was to investigate the role of AGEs and diabetes on the epigenetic modifications of EZH2 and H3K27me3 in proximal tubular cells and in diabetic (db/db) mice. Our results show that AGEs reduced EZH2 expression in TKPTS cells, thereby decreasing the tri-methylation of H3K27. qRT-PCR analysis revealed upregulation of genes known to contribute to diabetic nephropathy and kidney injury as Ctgf, Snai1, and p27Kip1. Consistently, immunofluorescent staining of renal sections from db/db mice confirmed the reduction in H3K27me3 levels in proximal tubules compared to non-diabetic controls. In summary, we show that AGEs induce epigenetic changes in proximal tubular cells by suppressing EZH2, thereby facilitating the transcription of genes involved in progression of diabetic nephropathy. These results provide new insights into metabolic memory, a process in which prior poor glucose control triggers ongoing renal damage despite current normoglycemia.
Source: Cells
Authors: Lore Ludewig, Tzvetanka Bondeva, Marita Liebisch, Jonas Ihle, Ivonne Loeffler, Gunter Wolf
Institution: Jena University Hospital
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W4415853948