Abstract
Autophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.
Highlights
acute kidney injury (AKI), which is defined as sudden kidney failure followed by sudden kidney damage, is independently associated with an increased risk of death and the development of chronic kidney disease (CKD) and end stage renal disease (ESRD)[1,2]
The expression levels of the autophagy-related proteins ATG7 and Becn[1] and the LC3 II/I ratio were increased in the I/R injury group compared with the sham group
These results suggest that farnesoid X receptor (FXR) was downregulated and the protein expression of autophagy-related proteins was increased in the I/R-induced AKI mouse model and hypoxia-treated HK2 cells
Summary
AKI, which is defined as sudden kidney failure followed by sudden kidney damage, is independently associated with an increased risk of death and the development of CKD and end stage renal disease (ESRD)[1,2]. The induction of autophagy in tubular epithelial cells has been documented in rodent models of AKI induced by renal I/R injury, nephrotoxic drugs, such as cisplatin, sepsis, and other AKI risk factors[3,4]. AKI induces cell death pathway activation through apoptotic and necrotic mechanisms in tubular epithelial cells[5]. Despite these studies, the principles of the regulatory mechanisms of autophagy and apoptosis in the progression from AKI to CKD are poorly understood. Autophagy, which is associated with several diseases and must be tightly controlled to maintain cellular homeostasis, is known to occur based on the response to either intracellular or extracellular factors, such as extremely stressful starvation conditions, hypoxia, Official journal of the Cell Death Differentiation Association
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