Abstract
Acute kidney injury (AKI) induced by ischemia-reperfusion is a critical conundrum in many clinical settings. Here, this study aimed to determine whether and how RTA-408, a novel oleanane triterpenoid, could confer protection against renal ischemia-reperfusion injury (IRI) in male mice. Mice treated with RTA-408 undergoing unilateral ischemia followed by contralateral nephrectomy had improved renal function and histological outcome, as well as decreased apoptosis, ROS production, and oxidative injury marker compared with vehicle-treated mice. Also, we had found that RTA-408 could strengthen the total antioxidant capacity by increasing Nrf2 nuclear translocation and subsequently increased Nrf2 downstream GSH-related antioxidant gene expression and activity. In vitro study demonstrated that GSH biosynthesis enzyme GCLc could be an important target of RTA-408. Furthermore, Nrf2-deficient mice treated with RTA-408 had no significant improvement in renal function, histology, ROS production, and GSH-related gene expression. Thus, by upregulating Nrf2 and its downstream antioxidant genes, RTA-408 presents a novel and potential approach to renal IRI prevention and therapy.
Highlights
Acute kidney injury (AKI) is a global public health concern which impacts approximately 13.3 million patients per year [1]
The left kidney tissues harvested at 24 h or 96 h postischemia were fixed in 10% buffered formalin, embedded in paraffin, and sectioned in fourmicrometer slices
Two experienced pathologists who were blinded to the experimental design scored the histopathological changes in the cortex and outer medulla with periodic acid Schiff (PAS) staining at 24 h, according to the necrotic tubule percentage in five randomly chosen, nonoverlapping high-power fields (HPF) at 400x magnification: 0, 1 (≦10%), 2 (11%–25%), 3 (26%–75%), and 4 (≧76%)
Summary
Acute kidney injury (AKI) is a global public health concern which impacts approximately 13.3 million patients per year [1]. Ischemia-reperfusion injury (IRI), which presents in numerous clinical conditions including renal transplantation, partial nephrectomy, shock, cardiac surgery, and vascular surgery, is a major cause of AKI in native kidneys, associating with high morbidity, increased Medicare costs, and high mortality (approximately 1.7 million deaths per year) [2, 3]. Oxidative stress (OS) substantially contributes to the pathophysiological process of renal IRI. Besides the direct oxidizing effect, ROS can initiate many other pathophysiological processes of IRI, including neutrophil infiltration [7, 8], apoptosis [9], endoplasmic reticulum stress [10], mitochondrial dysfunction [11], and endothelial activation [12]. Oxidative Medicine and Cellular Longevity these factors that can control the ROS detoxification may be potential therapeutic targets
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