Abstract
Remote ischemic preconditioning (RIPC) is an adaptive response, manifesting when local short-term ischemic preconditioning reduces damage to adjacent or distant tissues or organs. O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation of intracellular proteins denotes a type of posttranslational modification that influences multiple cytoplasmic and nuclear protein functions. Growing evidence indicates that stress can induce an acute increase in O-GlcNAc levels, which can be cytoprotective. The current study aimed to determine whether RIPC can provide renoprotection against contrast-induced acute kidney injury (CI-AKI) by augmenting O-GlcNAc signaling. We established a stable model of CI-AKI using 5/6 nephrectomized rats exposed to dehydration followed by iohexol injection via the tail vein. We found that RIPC increased UDP-GlcNAc levels through the hexosamine biosynthetic pathway as well as global renal O-GlcNAcylation. RIPC-induced elevation of O-GlcNAc signaling ameliorated CI-AKI based on the presence of less tubular damage and apoptosis and the amount of reactive oxygen species. In addition, the use of alloxan, an O-GlcNAc transferase inhibitor, and azaserine, a glutamine fructose-6-phosphate amidotransferase inhibitor, neutralized the protective effect of RIPC against oxidative stress and tubular apoptosis. In conclusion, RIPC attenuates local oxidative stress and tubular apoptosis induced by contrast exposure by enhancing O-GlcNAc glycosylation levels; this can be a potentially useful approach for lowering the risk of CI-AKI.
Highlights
The number of patients at risk of developing contrastinduced acute kidney injury (CI-AKI) is growing, owing to the popularity of iodinated contrast media (CM) use for different imaging studies
Existing studies suggest that CI-AKI develops in 2%–50% of individuals undergoing coronary artery angiography, and the incidence varies depending on the presence of different risk factors, including advanced age, chronic kidney disease (CKD), and diabetes [1]; among those who receive contrast-enhanced computed tomography, the incidence can be higher than 10% [2]
The renal pathology in the normal saline (NS) group only showed a reduction in renal glomerular, tubular, and interstitial fibrosis (Figure 1(b)). In addition to these pathological manifestations of chronic kidney disease (CKD), the CI-AKI model presented tubular injury induced by CM, manifesting as diffuse vacuolar degeneration and tubular necrosis, accompanied by tubular epithelial exfoliation
Summary
The number of patients at risk of developing contrastinduced acute kidney injury (CI-AKI) is growing, owing to the popularity of iodinated contrast media (CM) use for different imaging studies. Remote ischemic preconditioning (RIPC) is a revolutionary therapeutic modality, consisting of intermittent practices of repeated ischemia coupled with reperfusion, which was found to protect distant organs from developing such injury. This approach has been controversial since several recent randomized controlled trials reported contradictory findings [3, 4]. RIPC is thought to activate several pathways, including systemic anti-inflammatory, neuronal, and humoral signaling [6], but the underlying mechanisms are likely complex and have not been fully elucidated
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