Alteration of autophagy-related protein 5 (ATG5) levels and Atg5 gene expression in diabetes mellitus with and without complications

Abstract

Background Autophagy is a catabolic mechanism that involves lysosomal-dependent degradation of unnecessary intracellular components and responsible for normal cellular homeostasis. Autophagy pathway and its key participant ATG5/LC3 are associated with several pathologies such as diabetes mellitus and its complications. Methods Levels and expression of autophagy key components ATG5 and LC3B were analyzed in both human model and murine tissues. One hundred and twenty human subjects were divided into four groups: Healthy (control), diabetes mellitus without complications, diabetic nephropathy, and diabetic retinopathy. Additionally, we used kidneys from WT healthy and diabetic nephropathy mice. Lysate derived from human peripheral blood mononuclear cells and murine renal cortex lysates were subjected to western blot and immunohistochemical analysis. Results Western blot and immunohistochemical analysis demonstrate that ATG5 protein levels were significantly decreased in diabetes mellitus, diabetic nephropathy (DN), and diabetic retinopathy patients versus healthy controls and in DN mice compared to healthy mice (0.65 ± 0.04; 1.15 ± 0.13 A.U. units, respectively). Quantification of staining area (%) of ATG5 mice tissue expression also decreased in DN versus healthy mice (4.42 ± 1.08%; 10.87 ± 1.01%, respectively). LC3B levels and expression Significant reduction in peripheral blood mononuclear cells in diabetic patients (with or without complications) vs. healthy controls. Renal LC3B levels were lower in DN versus healthy mice (0.36 ± 0.03; 0.68 ± 0.07 A.U. units). Renal LC3B staining quantification revealed significant reduction in DN versus healthy mice (1.7 ± 0.23%; 8.56 ± 1.7%). Conclusion We conclude that ATG5, as well as LC3B, are down regulated in diabetic patients with or without complications. This diminution contributes to deficiencies in the autophagy process.

Research progress on the relationship between autophagy and chronic complications of diabetes

“…Furthermore, ATG, whose aberrant expression can induce disease, play important functions in different autophagic processes such as cytoplasmic encapsulation, autophagic vesicle formation and lysosomal fusion ( Levine and Kroemer, 2019 ; Mizushima and Levine, 2020 ). ATG5 and LC3 are key genes of autophagy and their levels are obviously lower in diabetic nephropathy (DN) model mice than those in normal group, which affects autophagy ( Yassin et al, 2021 ). Autophagy is an essential regulatory mechanism in diabetes, where the serum levels of the ATG protein Beclin-1 are inversely correlated with carotid intima-media thickness in patients with type 2 diabetes (T2D) ( Naguib et al, 2021 ).…”

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“…The soluble αKL is expressed in multiple tissues, with particularly high levels in the kidney and retina [13], and acts as a humoral factor that targets multiple tissues and organs with antiaging effects, anti-inflammatory and antioxidant activity [26][27][28]. Different studies suggest that klotho protein, which decreased in early stages of DN, and has an important role in the pathogenesis of DM and its vascular complications such as DR [11].…”

Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes

“…The autophagy process is mediated by autophagy-related genes (ARGs). For instance, ATG5 and LC3B are found to be decreased in diabetes mellitus patients with or without complications, indicating that downregulated ATG5 and LC3B may be implicated in the deficiencies of autophagy ( 15 ). A recent study has deciphered that upregulated ARGs such as Atg16L1, Atg16L2, and GabarapL1 are closely associated with the comorbidity of Alzheimer’s disease and T2DM ( 16 ).…”