Autophagy Functions to Prevent Methylglyoxal-Induced Apoptosis in HK-2 Cells.

So-Hyun Park,Yoon-Sook Kim,Hyun-Il Choi,Tae-Youl Ha,Hyo-Deok Seo,Young-Jin Jang,Chang Hwa Jung,Dae-Hee Lee,Jiyun Ahn

doi:10.1155/2020/8340695

Abstract

Methylglyoxal (MGO), a reactive carbonyl species, causes cellular damage and is closely related to kidney disease, particularly diabetic nephropathy. Although MGO has been reported to induce autophagy and apoptosis, the relationships between the two pathways are unclear. Here, we evaluated whether autophagy may be the underlying mechanism inhibiting MGO-induced apoptosis. MGO treatment induced concentration- and time-dependent apoptosis in HK-2 cells. Moreover, MGO upregulated the autophagy markers p62 and LC3-II. Apoptosis caused by MGO was increased in ATG5-knockdown cells compared to that in wild-type cells. In contrast, autophagy activation by 5-aminoimidazole-4-carboxamide ribonucleotide resulted in reduced apoptosis, suggesting that autophagy played a role in protecting against MGO-induced cell death. To examine the mechanisms through which autophagy occurred following MGO stimulation, we investigated changes in AKT/mammalian target of rapamycin (mTOR) signaling. Autophagy induction by MGO treatment was not related to AKT/mTOR signaling; however, it did involve autophagy-related gene expression promoted by AMP-activated protein kinase-mediated transcription factors, such as forkhead box 1. Overall, our findings indicate that MGO-induced cellular damage can be mitigated by autophagy, suggesting that autophagy may be a potential therapeutic target for diseases such as diabetic nephropathy.

Highlights

Methylglyoxal (MGO), a reactive carbonyl species, is formed in the glycolytic pathway following fragmentation of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate [1]
Our findings indicate that MGO-induced cellular damage can be mitigated by autophagy, suggesting that autophagy may be a potential therapeutic target for diseases such as diabetic nephropathy
These results indicate that treatment with 0.75 mM MGO for 24 h in HK-2 cells induced apoptosis in approximately 40% of the cells

Summary

Introduction

Methylglyoxal (MGO), a reactive carbonyl species, is formed in the glycolytic pathway following fragmentation of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate [1]. A recent study revealed that MGO is related to the early progression of diabetic nephropathy, the molecular mechanisms of the cytotoxic effects of MGO in kidney cells remain unclear [14]. Previous studies have shown that autophagy alleviates cell death in a variety of stress environments, including starvation, oxidative stress, and DNA damage [16,17,18]. Autophagy inducers, such as 5-aminoimidazole-4carboxamide ribonucleotide (AICAR) and rapamycin, block various stress-induced cell death pathways, suggesting a correlation between MGO-induced autophagy and apoptosis [19, 20]. Autophagy activation in human brain microvascular epidermal cells protects against MGO-induced cell

Methods

Results

Discussion

Conclusion