Uncoupling protein 2 (UCP2), an anion transporter, modulates the production of mitochondrial reactive oxygen species (ROS) and plays an important role in protecting against cell apoptosis. However, the role of UCP2 in sepsis-associated AKI remains unclear. In the present study, we investigated the role of UCP2 in LPS-induced AKI in vitro and in vivo. UCP2 expression was increased in tubular epithelial cells (TECs) treated with LPS. Accordingly, UCP2 expression was distinctly upregulated in renal tissues from the animals with LPS-induced AKI. Furthermore, UCP2 silencing dramatically aggravated LPS-induced apoptosis, accompanied by increased ROS production in renal tubular epithelial cell. Additionally, the inhibition of UCP2 by genipin, a specific UCP2 inhibitor, exacerbated the kidney injury of animals with LPS-induced AKI. Moreover, NAC (N-acetylcysteine), a potent ROS scavenger, obviously suppressed apoptosis induced by UCP2 silencing, which suggests that the increased ROS levels were associated with tubular epithelial cell apoptosis induced by UCP2 silencing. Therefore, UCP2 exerts a protective effect on the LPS-induced apoptosis of tubular epithelial cells by reducing excess ROS production. In conclusion, our findings highlight the renoprotective actions of UCP2 on inhibiting the production of apoptotic factors and oxidative stress to improve tubular cell survival in the LPS-induced AKI model.

Chronic kidney disease (CKD) is often accompanied by dyslipidemia, and abnormal lipid metabolism in proximal tubule cells is considered closely related to the dysfunction of proximal tubule cells and eventually leads to accelerated kidney damage. Nuclear factor E2-related factor 2 (Nrf2), known as a redox-sensitive transcription factor, is responsible for regulating cellular redox homeostasis. However, the exact role of Nrf2 in dyslipidemia-induced dysfunction of proximal tubule cells is still not fully elucidated. In the present study, we showed that palmitic acid (PA) induced mitochondrial damage, excessive mitochondrial reactive oxygen species (ROS) (mtROS) generation, and cell injury in HK-2 cells. We further found that mtROS generation was involved in PA-induced mitochondrial dysfunction, cytoskeletal damage, and cell apoptosis in HK-2 cells. In addition, we demonstrated that the Nrf2/ARE signaling pathway was activated in PA-induced HK-2 cells and that silencing Nrf2 dramatically aggravated PA-induced mtROS production, mitochondrial damage, cytoskeletal damage and cell apoptosis in HK-2 cells. However, the mitochondrial antioxidant MitoTEMPOL effectively eliminated these negative effects of Nrf2 silencing in HK-2 cells under PA stimulation. Moreover, activation of the Nrf2/ARE signaling pathway with tBHQ attenuated renal injury, significantly reduced mtROS generation, and improved mitochondrial function in rats with HFD-induced obesity. Taken together, these results suggest that the Nrf2/ARE-mediated antioxidant response plays a protective role in hyperlipidemia-induced renal injury by ameliorating mtROS-mediated mitochondrial dysfunction and that enhancing Nrf2 antioxidant signaling provides a potential therapeutic strategy for kidney injury in CKD with hyperlipidemia.

Recent evidence suggested that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in the pathogenesis of vascular calcification (VC). In this study, we tried to explore the e...