# Advanced Glycation End Products Mediate Epigenetic Alteration of H3K27me3 in Renal Proximal Tubular Cells: Potential Role in Metabolic Memory

## TL;DR

This study shows how advanced glycation end products (AGEs) cause epigenetic changes in kidney cells, contributing to diabetic kidney disease and long-term damage even after blood sugar levels normalize.

## Contribution

The study reveals a novel epigenetic mechanism involving EZH2 and H3K27me3 in proximal tubular cells, linking AGEs to diabetic nephropathy and metabolic memory.

## Key findings

- AGE-BSA reduces EZH2 and H3K27me3 in proximal tubular cells, increasing injury-related gene expression.
- Pharmacological EZH2 inhibition with DZNep mimics and enhances these effects in vitro and in diabetic mice.
- Diabetic mice show reduced H3K27me3 in proximal tubules with sex-specific differences in EZH2 expression.

## Abstract

What are the main findings?
AGE-BSA reduces EZH2 expression and the repressive histone mark H3K27me3 in proximal tubular TKPTS cells, leading to increased expression of genes involved in renal injury, including Ctgf, Snai1, and p27Kip1.Pharmacological inhibition of EZH2 with DZNep mimics and enhances these effects, and in vivo studies show reduced H3K27me3 in proximal tubules of diabetic mice, with sex-specific differences in EZH2 expression.

AGE-BSA reduces EZH2 expression and the repressive histone mark H3K27me3 in proximal tubular TKPTS cells, leading to increased expression of genes involved in renal injury, including Ctgf, Snai1, and p27Kip1.

Pharmacological inhibition of EZH2 with DZNep mimics and enhances these effects, and in vivo studies show reduced H3K27me3 in proximal tubules of diabetic mice, with sex-specific differences in EZH2 expression.

What is the implication of the main finding?
The suppression of EZH2 by AGEs represents an epigenetic mechanism contributing to proximal tubular cell damage and the progression of diabetic nephropathy.These results provide insight into metabolic memory, highlighting that prior hyperglycemia can induce persistent epigenetic changes and sex-specific vulnerabilities in the kidney, even under current normoglycemia.

The suppression of EZH2 by AGEs represents an epigenetic mechanism contributing to proximal tubular cell damage and the progression of diabetic nephropathy.

These results provide insight into metabolic memory, highlighting that prior hyperglycemia can induce persistent epigenetic changes and sex-specific vulnerabilities in the kidney, even under current normoglycemia.

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.