Abstract
BackgroundIschemia–reperfusion (I/R)-induced acute kidney injury (AKI) not only prolongs the length of hospital stay, but also seriously affects the patient’s survival rate. Although our previous investigation has verified that reactive oxygen species (ROS) transferred through gap junction composed of connexin32 (Cx32) contributed to AKI, its underlying mechanisms were not fully understood and viable preventive or therapeutic regimens were still lacking. Among various mechanisms involved in organs I/R-induced injuries, endoplasmic reticulum stress (ERS)-related apoptosis is currently considered to be an important participant. Thus, in present study, we focused on the underlying mechanisms of I/R-induced AKI, and postulated that Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI.MethodsWe established renal I/R models with Cx32+/+ and Cx32−/− mice, which underwent double kidneys clamping and recanalization. ROS scavenger (N-acetylcysteine, NAC) and ERS inhibitors (4-phenyl butyric acid, 4-PBA, and tauroursodeoxycholic acid, TUDCA) were used to decrease the content of ROS and attenuate ERS activation, respectively.ResultsRenal damage was progressively exacerbated in a time-dependent manner at the reperfusion stage, that was consistent with the alternation of ERS activation, including glucose regulated protein 78 (BiP/GRP78), X box-binding protein1, and C/EBP homologous protein expression. TUDCA or 4-PBA application attenuated I/R-induced ERS activation and protected against renal tubular epithelial cells apoptosis and renal damage. Cx32 deficiency decreased ROS generation and distribution between the neighboring cells, which attenuated I/R-induced ERS activation, and improved cell apoptosis and renal damage.ConclusionCx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI. Cx32 deficiency, ROS elimination, and ERS inhibition all could protect against I/R-induced AKI.
Highlights
Ischemia–reperfusion (I/R)-induced acute kidney injury (AKI) prolongs the length of hospital stay, and seriously affects the patient’s survival rate
Changes of I/R‐induced renal injury and cell apoptosis were consistent with endoplasmic reticulum stress (ERS) activation Dynamic renal injuries were observed at different time points after renal I/R, which got to the peak at 24 h after renal I/R, manifested as severe pathological damage and functional impairment, and significant increase of Cr and blood urea nitrogen (BUN)
Results indicated that ERS related proteins, such as GRP78, X box-binding protein 1 (XBP1) and C/EBP homologous protein (CHOP) in renal tissues, were all increased as reperfusion time extended and peaked at 16 or 24 h after reperfusion, which mirrored the patterns of pathological damage and functional impairment (Fig. 1e)
Summary
Ischemia–reperfusion (I/R)-induced acute kidney injury (AKI) prolongs the length of hospital stay, and seriously affects the patient’s survival rate. Our previous investigation has verified that reactive oxygen species (ROS) transferred through gap junction composed of connexin (Cx32) contributed to AKI, its underlying mechanisms were not fully understood and viable preventive or therapeutic regimens were still lacking. Among various mechanisms involved in organs I/R-induced injuries, endoplasmic reticulum stress (ERS)-related apoptosis is currently considered to be an important participant. In a large amount of clinical settings, such as renal artery reconstruction, cardiac bypass surgery, partial nephrectomy, shock, and kidney transplantation, I/R-induced renal damage has been considered to be one of the most important causes that contribute to AKI [4, 5]. The clinical outcome of AKI is closely related to the severity of I/R-induced injury. Many potential mechanisms of I/R-induced AKI have been explored, viable preventive or therapeutic regimens are still lacking
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