The Effect of Allograft Inflammatory Factor-1 on Inflammation, Oxidative Stress, and Autophagy via miR-34a/ATG4B Pathway in Diabetic Kidney Disease

Abstract

Increasing evidence suggests that disorders of inflammation, oxidative stress, and autophagy contribute to the pathogenesis of diabetic kidney disease (DKD). This study attempted to clarify the effect of allograft inflammatory factor-1 (AIF-1), miR-34a, and ATG4B on inflammation, oxidative stress, and autophagy in DKD both in vitro and in vivo experiments. In vivo, it was found that the levels of AIF-1, miR-34a, oxidative stress, and inflammatory factors were significantly increased in blood and urine samples of DKD patients and mouse models and correlated with the level of urinary protein. In vitro, it was also found that the expressions of AIF-1, miR-34a, ROS, and inflammatory factors were increased, while ATG4B and other autophagy related proteins were decreased in human renal glomerular endothelial cells (HRGECs) cultured with high concentration glucose medium (30 mmol/L). When AIF-1 gene was overexpressed, the levels of miR-34a, ROS, and inflammatory factors were significantly upregulated, and autophagy-related proteins such as ATG4B were downregulated, while downregulation of AIF-1 gene had the opposite effect. In addition, miR-34a inhibited the expression of ATG4B and autophagy-related proteins and increased the levels of ROS and inflammation. Furthermore, the result of luciferase reporter assay suggested that ATG4B was the target gene of miR-34a. When ATG4B gene was overexpressed, the level of autophagy was upregulated, and inflammatory factors were downregulated. Conversely, when ATG4B gene was inhibited, the level of autophagy was downregulated, and inflammatory factors were upregulated. Then, autophagy inducers inhibited the levels of inflammation and ROS, whereas autophagy inhibitors had the opposite function in HRGECs induced by glucose (30 mmol/L). In conclusion, the above data suggested that AIF-1 regulated the levels of inflammation, oxidative stress, and autophagy in HRGECs via miR-34a/ATG4B pathway to contribute to the pathogenesis of diabetic kidney disease.

AIF1: Function and Connection with Inflammatory Diseases

“…Indeed, downregulation of AIF1 reversed pathological damage, renal inflammation, and oxidative stress in a DKD murine model. AIF1 has also been linked to inflammation, oxidative stress and autophagy via the miR-34a/autophagy-related gene 4B (ATG4B) pathway [105]. miR-34a targets the 3 untranslated region of ATG4B mRNA and inhibits its translation [106,107].…”

“…miR-34a targets the 3 untranslated region of ATG4B mRNA and inhibits its translation [106,107]. In human renal glomerular endothelial cell (HRGEC) culture, AIF1 overexpression or silencing upregulates or downregulates miR-34a and downregulates or upregulates ATG4B, respectively [105]. Additionally, glucose induced the expression of AIF-1, miR-34a and reactive oxygen species (ROS) and inhibited ATG4B expression.…”

Autophagy and its therapeutic potential in diabetic nephropathy

“…Severe damage to the glomerular endothelium owing to autophagy reduction has been reported in endothelial-specific autophagy-deficient mice and Atg16L-knockdown GEnCs ( 88 , 89 ). In addition, activation of calcium/calmodulin-dependent protein kinase kinase β (CAMKKβ)/liver kinase B1 (LKB1)/AMPK signaling ( 60 ) and inhibition of miR-34a/Atg4b signaling ( 61 ) promote autophagy in GEnCs to attenuate DN. It is well established that the interplay of podocytes, GEnCs, and GMCs is key to keep the integrity of the GFB and the pathological alteration in one component evidently affects the other two ( 87 , 90 , 91 ).…”

“…• Promotion of autophagy by inhibiting miR-34a/Atg4b pathway in glomerular endothelial cells relieves diabetic kidney damage (61).…”

Exosomal lincRNA-p21/AIF-1 promoted inflammation of human tubular epithelial cell via CMPK2/NLRP3 pathway in urate nephropathy

“…On the other hand, allograft in ammatory factor 1 (AIF-1) is a calcium-binding cytoplasmic scaffold protein observed in several in ammatory diseases, including atherosclerosis, rheumatoid arthritis, renal tubulointerstitial brosis, vascular calci cation, and diabetic kidney disease [15,16,17,18,19]. Our group has conducted a series of studies on AIF-1 and con rmed its role in promoting in ammation and brosis in the renal tubulointerstitium.…”