Abstract
The aim of our study was to investigate the role of autophagy, a homeostatic process involved in the lysosomal degradation of damaged cell organelles and proteins, in regulating the survival of mesangial cells treated with advanced glycation end products (AGEs). In the present study, AGEs induced mitochondrial depolarization and led to mitochondrial-dependent apoptosis in mesangial cells, as shown by the loss of the mitochondrial membrane potential; increased Bax processing; increased Caspase-9, Caspase-3 and PARP cleavage; and decreased Bcl-2 expression. Meanwhile, AGEs also triggered autophagy flux in mesangial cells, as confirmed by the presence of autophagic vesicles, the conversion of LC3II/LC3I and the increase/decrease in Beclin-1/p62 expression. Interestingly, this study reported apparent apoptosis and autophagy that were dependent on reactive oxygen species (ROS) production. Scavenging ROS with N-acetyl-l-cysteine could prevent the appearance of the autophagic features and reverse AGE-induced apoptosis. Moreover, AGE-triggered mitophagy, which was confirmed by the colocalization of autophagosomes and mitochondria and Parkin translocation to mitochondria, played a potential role in reducing ROS production in mesangial cells. Additionally, inhibition of autophagy significantly enhanced AGE-induced cell apoptosis. Taken together, our data suggest that ROS were the mediators of AGE-induced mesangial cell apoptosis and that autophagy was likely to be the mechanism that was triggered to repair the ROS-induced damage in the AGE-treated cells and thereby promote cell survival. This study provides new insights into the molecular mechanism of autophagy involved in AGE-induced apoptosis in mesangial cells.
Highlights
The number of people with diabetes will increase from 382 million in 2013 to 592 million by 2035 worldwide, with 80% of cases occurring in low-income and middle-income countries of the International Diabetes Federation (IDF) Diabetes Atlas.[1]
Studies have suggested that mesangial cell apoptosis is correlated with worsening albuminuria,[2] and that the loss of mesangial cells through apoptosis contributes to diabetic glomerulosclerosis, which is involved in the pathogenesis and progression of Diabetic nephropathy (DN).[3,4]
The data from the cell death detection ELISAPLUS assay showed that Advanced glycation end products (AGEs) (200 mg/l) treatment for 24 h increased the DNA fragmentation ratio compared with the control group (Po0.05) and showed the most significant increase with 250 mg/l AGEs (Po0.01) (Figure 1b)
Summary
The number of people with diabetes will increase from 382 million in 2013 to 592 million by 2035 worldwide, with 80% of cases occurring in low-income and middle-income countries of the International Diabetes Federation (IDF) Diabetes Atlas.[1]. Glomerular mesangial cells are known to play an important role in maintaining both the structure and functions of glomerular tufts. Numerous data indicate that AGEs play an important role in the pathogenesis of DN.[6,7,8] Patients with DN exhibit increased serum AGEs levels and decreased clearance.[9]. Immunohistochemical studies in patients with DN have shown that AGEs accumulate in the mesangium and glomerular capillary wall.[10] In addition, both in vivo and in vitro studies showed that AGEs induce mesangial cell dysfunction and lead to apoptosis, which disturbs glomerular homeostasis and is involved in the pathogenesis of DN.[11,12,13] the exact mechanisms of AGE-induced mesangial cell apoptosis are still unclear. We investigated the molecular mechanism of mesangial
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