Background
The deactivation of SIRT3, a novel deacetylase located in mitochondria, can aggravate multiple organ dysfunction. However, the role of SIRT3 and its downstream targets in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) remain unknown. Materials and
Conclusions
The elevation of SOD2 and p53 protein acetylation in the mitochondria of renal tubular epithelial cells is an important signaling event in the pathogenesis of I/R-induced AKI. Thus, deacetylase SIRT3 may be an upstream regulator of both SOD2 and p53, and the SIRT3 deactivation may aggravate AKI.
Methods
I/R was reproduced in a rat model using a clamp placed on the left and right renal pedicles for 40 min. The rats were intraperitoneally injected with either the vehicle or a selective SIRT3 inhibitor (3-TYP) and scarified at different time points (4, 8, and 24 h after I/R). A portion of the renal tissue was extracted for histological analysis, and another portion was collected for the isolation of renal tubular epithelial cells for Western blotting, SOD2 and SIRT3 activity, cell apoptosis, and the determination of oxidative stress.
Results
The I/R-induced AKI model was successfully reproduced and SIRT3 activity was considerably reduced than control (sham operated) group, accompanied by increased acetylation of SOD2 and p53, as well as their elevated physical interaction in extracted mitochondrial protein (all P values < 0.05). Moreover, SIRT3 suppression by 3-TYP treatment (comparing with the vehicle treatment group) aggravated AKI, as evidenced by increased indicators of oxidative stress (increased mitochondrial red fluorescence MitoSOX and decreased reduced glutathione/oxidized glutathione ratio, all P values < 0.01). Conclusions: The elevation of SOD2 and p53 protein acetylation in the mitochondria of renal tubular epithelial cells is an important signaling event in the pathogenesis of I/R-induced AKI. Thus, deacetylase SIRT3 may be an upstream regulator of both SOD2 and p53, and the SIRT3 deactivation may aggravate AKI.