Stimulation of AMPK Prevents Diabetes‐Induced Photoreceptor Cell Degeneration

Abstract

Diabetic retinopathy (DR) is a kind of severe retinal neurodegeneration. The advanced glycation end products (AGEs) affect autophagy, and mitochondrial function is involved in DR. Adenosine-activated protein kinase (AMPK) is an important metabolic sensor that can regulate energy homeostasis in cells. However, the effect of AMPK in DR is still not fully understood. In this study, we investigated the effect of AMPK on diabetes-induced photoreceptor cell degeneration. In vivo, a diabetic mouse model was established by streptozotocin (STZ) injection. Haematoxylin-eosin (HE) staining was used to observe retinal morphology and measure the thicknesses of different layers in the retina. Electroretinogram (ERG) was used to evaluate retinal function. In vitro, 661w cells were treated with AGEs with/without an AMPK agonist (metformin) or AMPK inhibitor (compound C). Flow cytometry and CCK-8 assays were used to analyse apoptosis. Mitochondrial membrane potential was analysed by JC-1. Western blotting and qRT-PCR were used to examine the expression of related proteins and genes, respectively. The wave amplitude and the thickness of the outer nuclear layer were decreased in diabetic mice. The expression of rhodopsin and opsin was also decreased in diabetic mice. In vitro, the percentage of apoptotic cells was increased, the expression of the apoptosis-related protein Bax was increased, and Bcl-2 was decreased after AGE treatment in 661w cells. The expression of the autophagy-related protein LC3 was decreased, and p62 was increased. The mitochondrial-related gene expression and membrane potential were decreased, and mitochondrial morphology was abnormal, as observed by TEM. However, AMPK stimulation ameliorated this effect. These results indicate that AMPK stimulation can delay diabetes-induced photoreceptor degeneration by regulating autophagy and mitochondrial function.

Role of AMPK in autophagy

“…Specifically, AMP first stimulates the phosphorylation of Thr172 by directly activating upstream kinases (Kim et al, 2020). Thr172 can be phosphorylated by several different upstream kinases, which establishes the main mechanism by which AMPK activity is regulated in the short term (Song et al, 2021). Different studies have suggested that LBK1 (liver kinase B1) kinase and MAPKKK family member TAK/MAP3K7 (transforming growth factor beta-activated kinase 1/mitogen-activated kinase 7) can respond to various signals by phosphorylating Thr172 (Fritzen et al, 2016).…”

Diabetic retinopathy: Involved cells, biomarkers, and treatments

“…The two types of photoreceptor cells are rod cells, which contain rhodopsin that facilitates vision at night, and cone cells, which contain a cone pigment and are sensitive to high light. In hyperglycemia, rhodopsin expression decreases, and rod cells are more sensitive to hyperglycemia ( Yang M. et al, 2021 ; Song et al, 2021 ).…”

Altered Expressions of Transfer RNA-Derived Small RNAs and microRNAs in the Vitreous Humor of Proliferative Diabetic Retinopathy

“…It has been reported that the AMPK signaling pathway is involved in the etiopathogenesis of many ocular diseases, including DR (30). Song et al demonstrated that stimulation of AMPK signaling pathway attenuate diabetes-induced photoreceptor degeneration through regulation of autophagy and mitochondrial function (31). AMPK phosphorylation is required in the regulation of HMGB1 induced by Epac1 in the diabetic retinal vasculature (32).…”