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

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.

Metastatic Prostate Cancer Cells Secrete Methylglyoxal-Derived MG-H1 to Reprogram Human Osteoblasts into a Dedifferentiated, Malignant-like Phenotype: A Possible Novel Player in Prostate Cancer Bone Metastases

“…MG-H1 can signal through receptor for AGEs (RAGE) [ 15 ] to trigger ROS intracellular accumulation that, in turn, actives NF-kB pathway [ 17 ]. Hence, we investigated whether MG-H1-induced OB dedifferentiation occurred through a RAGE-dependent mechanism, possibly involving reactive oxidative species (ROS) and the NF-kB pathway.…”

“…It is known that NF-kB can trigger ROS formation [ 14 , 16 ]. Similarly, emerging evidence shows that ROS can activate the NF-kB pathway [ 17 ] so that a strong interplay exists between these two actors, which, for this, are not mutually exclusive. Hence, we would like to point out that once MG-H1/RAGE complex is formed and drives ROS and NF-kB production/activation, it is also possible that a concomitant amplification of the downstream effects on OB dedifferentiation might occur due to ROS/NF-kB-positive feed-forward loop within a precise regulatory circuitry.…”

“…Importantly, upon MG-H1-containing PC3 CM exposure, blockade of RAGE with the high-affinity RAGE-specific inhibitor FPS-ZM1 [41,42], rescued OB dedifferentiation and re-wiring, evaluated by VIM, CADH11, Runx 2, CD44, migration, and PSMA levels (Figure 11d). [15] to trigger ROS intracellular accumulation that, in turn, actives NF-kB pathway [17]. Hence, we investigated whether MG-H1-induced OB dedifferentiation occurred through a RAGE-dependent mechanism, possibly involving reactive oxidative species (ROS) and the NF-kB pathway.…”

“…In general, engagement of RAGE by AGEs can activate transcription factor NF-kB, which increases reactive oxidative species (ROS) formation [ 14 , 16 ]. However, it has been recently demonstrated that the binding of AGEs with RAGE can also directly trigger ROS intracellular accumulation that in turn actives NF-kB pathway [ 17 ]. Of note, RAGE is expressed by OB [ 14 , 18 ], where it plays a pivotal role in bone metabolism [ 19 ].…”

Association of Novel Advanced Glycation End-Product (AGE10) with Complications of Diabetes as Measured by Enzyme-Linked Immunosorbent Assay

“…Moreover, AGEs activate parietal epithelial cells, leading to thickening of the Bowman’s capsule surrounding the glomerulus, altering the efficacy of renal filtration [ 35 ]. AGE4 causes mitochondrial dysfunction and stress in endoplasmic reticulum of nephrons [ 54 ]. Accumulation of AGEs results in renal toxicity which gradually reduces the kidney filtration and leads to chronic kidney disease [ 55 ].…”