Abstract
Ischemia–reperfusion (I/R) is the most common cause of acute kidney injury (AKI) and can induce apoptosis in renal epithelial tubule cells. Mitochondrial dysfunction is one of the main reasons for I/R-induced apoptosis. Accumulating evidence suggests that PINK1/Parkin-mediated mitophagy possibly plays a renoprotective role in kidney disease by removing impaired mitochondria and preserving a healthy population of mitochondria. Our previous study showed that augmenter of liver regeneration (ALR) alleviates tubular epithelial cells apoptosis in rats with AKI, although the specific mechanism remains unclear. In this study, we investigated the role of ALR in I/R-induced mitochondrial pathway of apoptosis. We knocked down ALR with short hairpin RNA lentiviral and established an I/R model in human kidney proximal tubular (HK-2) cells in vitro. We observed that the knockdown of ALR aggravated mitochondrial dysfunction and increased the mitochondrial reactive oxygen species (ROS) levels, leading to an increase in cell apoptosis via inhibition of mitophagy. We also found that the PINK1/Parkin pathway was activated by I/R via confocal microscopy and Western blot. Furthermore, the knockdown of ALR suppressed the activation of PINK1 and Parkin. These findings collectively indicate that ALR may protect HK-2 cells from I/R injury by promoting mitophagy, and the mechanism by which ALR regulates mitophagy seems to be related to PINK1 and Parkin. Consequently, ALR may be used as a potential therapeutic agent for AKI in the future.
Highlights
Acute kidney injury (AKI) is a common and severe renal disease characterized by a rapid loss of kidney function
We first showed that activation of augmenter of liver regeneration (ALR) and mitochondrial dysfunction were induced in ischemia reperfusion (I/R)-acute kidney injury (AKI) in vitro
We showed that a deficiency in ALR increased mitochondrial reactive oxygen species (ROS) production and mitochondrial deficiencies accompanied with inhibition of PINK1/Parkinson disease 2 (Parkin)-mediated mitophagy, contributing to cell apoptosis in I/R in vitro
Summary
Acute kidney injury (AKI) is a common and severe renal disease characterized by a rapid loss of kidney function. Anti-apoptosis Effect of ALR treatment is available; severe AKI is accompanied with a high mortality and has become a global public health issue and socioeconomic burden. A range of factors can lead to AKI, including ischemia reperfusion (I/R) injury, sepsis, and nephrotoxins (Mehta et al, 2016). Renal I/R is a main cause of AKI and is characterized by a reduction in the tissue blood supply, which causes acute tubular injury. Re-establishing the blood supply following prolonged ischemia stimulates vascular endothelial cells and enhances the generation of reactive oxygen species (ROS). The excessive production of ROS causes oxidative damage in renal tubular epithelial cells, leading to apoptosis or necrosis (Malek and Nematbakhsh, 2015)
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