Methylglyoxal-Derived Advanced Glycation End Product (AGE4)-Induced Apoptosis Leads to Mitochondrial Dysfunction and Endoplasmic Reticulum Stress through the RAGE/JNK Pathway in Kidney Cells.

So-Ra Jeong,Kwang-Won Lee

doi:10.3390/ijms22126530

Abstract

Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known about the function of methylglyoxal-derived AGEs (AGE4) in kidney cells. Therefore, we verified the expression of endoplasmic reticulum (ER) stress-related genes and apoptosis markers to determine the effects of AGE4 on human proximal epithelial cells (HK-2). Moreover, our results showed that AGE4 induced the expression of apoptosis markers, such as Bax, p53, and kidney injury molecule-1, but downregulated Bcl-2 and cyclin D1 levels. AGE4 also promoted the expression of NF-κB, serving as a transcription factor, and the phosphorylation of c-Jun NH2-terminal kinase (JNK), which induced cell apoptosis and ER stress mediated by the JNK inhibitor. Furthermore, AGE4 induced mitochondrial dysfunction by inducing the permeabilization of the mitochondrial membrane and ATP synthesis. Through in vitro and in vivo experiments, this study provides a new perspective on renal dysfunction with regard to the AGE4-induced RAGE /JNK signaling pathway, which leads to renal cell apoptosis via the imbalance of mitochondrial function and ER stress in kidney damage.

Highlights

Unlike type 1 diabetes, which is induced by an inherited disorder of insulin production in pancreatic islet β-cells [1], type 2 diabetes is caused by a variety of factors, including a lack of exercise, alcohol intake, genetic factors, and diet [2]
We used in vitro and in vivo models to investigate the involvement of the AGE4–receptors for advanced glycation end products (RAGE) axis and specific signaling pathways that induce Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which contribute to apoptosis
The following points are suggested in this study: (1) RAGE–AGE4 can cause ER stress that leads to apoptosis in kidney cells

Summary

Introduction

Unlike type 1 diabetes, which is induced by an inherited disorder of insulin production in pancreatic islet β-cells [1], type 2 diabetes is caused by a variety of factors, including a lack of exercise, alcohol intake, genetic factors, and diet [2]. Glyceraldehyde-derived AGEs induce apoptosis in human dermal fibroblasts by increasing reactive oxygen species (ROS) and activating the NLRP3 inflammasome [9]. We previously showed that the treatment of NRK-52E kidney cells with MGO-derived AGEs (AGE4) leads to an increase in the protein levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 via AGE4–RAGE interactions [12]. ER stress affects mitochondria directly or indirectly [18], the exact effects of AGE4 on the signaling pathways associated with ER stress and cell apoptosis are unknown. We used in vitro and in vivo models to investigate the involvement of the AGE4–RAGE axis and specific signaling pathways that induce ER stress and mitochondrial dysfunction, which contribute to apoptosis

Methods

Results

Conclusion