Abstract
Saturated free fatty acid (FFA)-induced lipotoxicity plays an important role in obesity-induced kidney injury. Exenatide, a Glucagon-like peptide-1 receptor agonist(GLP-1RA), protects against high-fat diet (HFD)-induced kidney injury. The precise mechanism needs to be further explored. This study investigated whether exenatide protects against FFA-induced tubular epithelial cells (TECs) lipotoxicity and elucidated its underlying mechanisms. Here, we show that exenatide treatment reversed HFD induced TECs injuries, including TECs apoptosis and SIRT1 downregulation. The efficacy of exenatide was better than simvastatin. In palmitate (PA)-stimulated HK2 cells, exenatide treatment reversed the downregulation of SIRT1 and prevented an increase in reactive oxygen species (ROS) production, a decrease in mitochondrial membrane potential, and mitochondrial apoptosis. The renal-protective effects of exenatide on the generation of mitochondrial ROS and mitochondrial apoptosis were blocked by inhibiting SIRT1 activation. Collectively, these findings show that exenatide was superior to simvastatin in the treatment of obesity-TECs injuries, the mechanism is partially through SIRT1 restoration, which directly reverses mitochondrial dysfunction and apoptosis.
Highlights
Obesity has emerged as an escalating public health problem, resulting in shortened life expectancy, lowered quality of life and increased medical expenditure [1]
To investigate the metabolic effects of exenatide in vivo, high-fat diet (HFD) mice were treated with exenatide, and simvastatin was used as a lipidlowering control
Treated with simvastatin only partly reverse tubular epithelial cells (TECs) dilation and vacuolation. Those changes were accessed by TIS, which were significantly elevated in the HFD groups, whereas were ameliorated after treatment with exenatide or simvastatin (Figure 1F)
Summary
Obesity has emerged as an escalating public health problem, resulting in shortened life expectancy, lowered quality of life and increased medical expenditure [1]. A close association between obesity and renal dysfunction has become apparent. Epidemiologic analyses have shown that obesity is an independent risk factor for chronic kidney disease (CKD) [2]. Obesity is characterized by elevated circulating free fatty acids (FFAs) and hypertriglyceridemia. Elevated FFAs and deleterious FFA‐derived lipids lead to metabolic disorders, cellular dysfunction, and cell death in nonadipose tissues, which is known as lipotoxicity [3]. Numerous studies have indicated that the overaccumulation of FFAs in the kidney induces podocyte, proximal tubular epithelial cells (TECs) and tubulointerstitial tissue damage through different mechanisms, by boosting the production of reactive oxygen species (ROS) and promoting mitochondrial damage and tissue inflammation [4]
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