microRNA-125b contributes to high glucose-induced reactive oxygen species generation and apoptosis in HK-2 renal tubular epithelial cells by targeting angiotensin-converting enzyme 2

OBJECTIVE: Hyperglycemia induces apoptosis of renal tubular epithelial cells and contributes to tubular injury in diabetic nephropathy. Angiotensin-converting enzyme 2 (ACE2) is known to protect against diabetic kidney injury. However, the mechanism for the dysregulation of ACE2 expression in diabetic nephropathy is unclear.

MATERIALS AND METHODS: Bioinformatic analysis and luciferase reporter assay were done to identify ACE2-targeting microRNAs. Gain- and loss-of-function experiments were performed to determine the biological roles of the ACE2-targeting microRNAs in high glucose-induced damage to renal tubular epithelial cells.

RESULTS: We identified microRNA-125b (miR-125b) as a negative regulator of ACE2. After high glucose treatment, HK-2 renal tubular epithelial cells showed an upregulation of miR-125b and reduction of ACE2 expression. Knockdown of miR-125b with anti-miR-125b inhibitors significantly prevented high glucose-induced downregulation of ACE2 in HK-2 cells. Moreover, depletion of miR-125b significantly blocked reactive oxygen species (ROS) formation and apoptosis in high glucose-exposed HK-2 cells. In contrast, ectopic expression of miR-125b accelerated ROS production and apoptotic response in HK-2 cells, which was coupled with induction of Bax and reduction of Bcl-2. Rescue experiments demonstrated that overexpression of ACE2 reversed the effects of miR-125b on ROS generation, apoptosis, and deregulation of Bcl-2 and Bax in HK-2 cells.

CONCLUSIONS: Taken together, miR-125b mediates high glucose-induced ROS production and apoptosis in HK-2 renal tubular epithelial cells, largely through targeting ACE2. Accordingly, miR-125b represents a potential therapeutic target for the prevention of diabetic nephropathy.

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