HMGB1 downregulation in retinal pigment epithelial cells protects against diabetic retinopathy through the autophagy-lysosome pathway

Abstract

Diabetic retinopathy (DR) is a serious complication of diabetes mellitus and currently one of the major causes of blindness. Several previous studies have demonstrated that autophagy, which is regulated by HMGB1 (high mobility group box 1), is involved in DR development. However, the role of autophagy in DR is quite complicated in that it promotes pericyte survival in early DR, whereas excessive autophagy causes excess stress and leads to necrosis. Therefore, this study aimed to investigate the relationship between HMGB1, the macroautophagy/autophagy-lysosome pathway, and DR, as well as their underlying molecular mechanisms. In brief, the relationship between high glucose (HG) and the autophagy-lysosome pathway was examined in retinal pigment epithelial (RPE) cells. The relationship was studied by detecting classical autophagic features, and siRNAs targeting HMGB1 and pharmacological regulators were used to explore the role of the autophagy-lysosome pathway in DR development. The results demonstrated that HG inhibited autophagy and diminished the degradative capacity of autophagy due to lysosome membrane permeabilization (LMP). In addition, HMGB1 was found to be involved in LMP via the CTSB (cathepsin B)-dependent pathway, but not the CTSL (cathepsin L)-dependent pathway. Knockdown of HMGB1 expression rescued LMP, restored the degradative capacity of autophagy, decreased the expression of inflammatory factors and VEGF (vascular endothelial growth factor), and protected against apoptosis in RPE cells in the early stages of DR.

Identification of Biomarkers of Autophagy-Related Genes Between Early and Advanced Carotid Atherosclerosis

“… 37 Furthermore, the degradative capacity restoration of autophagy decreased the expression of inflammatory factors and VEGF (vascular endothelial growth factor), and protected against apoptosis in retinal pigment epithelial cells in the early stages of diabetic retinopathy. 38 In line with the above study, the present study revealed a causal relationship between increased CTSB levels and advanced carotid atherosclerosis, which conformably occurred with coronary heart disease and diabetes. Similarly, we observed that the GO categories related to autophagy, pathways in cancer, apoptosis and viral process were all most significantly enriched in carotid atherosclerosis progression.…”

Exosomes From Human Umbilical Cord Mesenchymal Stem Cells Treat Corneal Injury via Autophagy Activation

“…This indicated that the cornea could not easily remove all impaired organelles and cytoplasmic contents to maintain a steady state via finite lysosomal pathways. Based on previous findings suggesting that autophagy is involved in regulating the ocular balance ( Feng et al, 2021 ), we speculate that the rate of CI healing is related to the expression level of autophagy. A suitable autophagic level is therefore conducive to the treatment and prognosis.…”

Chaperonin-Containing TCP1 Subunit 5 Protects Against the Effect of Mer Receptor Tyrosine Kinase Knockdown in Retinal Pigment Epithelial Cells by Interacting With Filamentous Actin and Activating the LIM-Kinase 1/Cofilin Pathway

“…The immunofluorescence assays were performed as previously described in Feng et al ( 64 ). HsRPE cells were fixed with 4% paraformaldehyde for 15 min, followed by blocking with 5% BSA at room temperature for 1 h. The cell samples were incubated with RPE65 (Abcam, ab235950), F-actin (Abcam, ab130935), CCT5 (Proteintech, 11603-1-AP), and MERTK (Cell Signaling Technology, 4319S) antibodies.…”