Abstract
Changes of metabolism have been implicated in renal ischemia/reperfusion injury (IRI). However, a global analysis of the metabolic changes in renal IRI is lacking and the association of the changes with ischemic kidney injury and subsequent recovery are unclear. In this study, mice were subjected to 25 minutes of bilateral renal IRI followed by 2 hours to 7 days of reperfusion. Kidney injury and subsequent recovery was verified by serum creatinine and blood urea nitrogen measurements. The metabolome of plasma, kidney cortex, and medulla were profiled by the newly developed global metabolomics analysis. Renal IRI induced overall changes of the metabolome in plasma and kidney tissues. The changes started in renal cortex, followed by medulla and plasma. In addition, we identified specific metabolites that may contribute to early renal injury response, perturbed energy metabolism, impaired purine metabolism, impacted osmotic regulation and the induction of inflammation. Some metabolites, such as 3-indoxyl sulfate, were induced at the earliest time point of renal IRI, suggesting the potential of being used as diagnostic biomarkers. There was a notable switch of energy source from glucose to lipids, implicating the importance of appropriate nutrition supply during treatment. In addition, we detected the depressed polyols for osmotic regulation which may contribute to the loss of kidney function. Several pathways involved in inflammation regulation were also induced. Finally, there was a late induction of prostaglandins, suggesting their possible involvement in kidney recovery. In conclusion, this study demonstrates significant changes of metabolome kidney tissues and plasma in renal IRI. The changes in specific metabolites are associated with and may contribute to early injury, shift of energy source, inflammation, and late phase kidney recovery.
Highlights
Acute kidney injury (AKI) is a major kidney disease characterized by a rapid decline of renal function
The change of specific metabolites may indicate the pathways that are critically important in the pathogenesis of renal ischemia/reperfusion injury (IRI) and subsequent recovery
Metabolomics has been introduced to study the changes in metabolism in AKI within the last a few years, especially in nephrotoxic models including those induced by gentamycin, cisplatin, nicotinic acid receptor agonist, melamine and cyanuric acid [2,4,5,6,7,8,9,10,11,12,13]
Summary
Acute kidney injury (AKI) is a major kidney disease characterized by a rapid decline of renal function. As the main function of kidney is to excrete the metabolic wastes and toxins, the loss of kidney function in AKI is expected to induce significant changes in various metabolites in the body, especially in the plasma of the blood [2]. While the study by Liu et al revealed interesting changes, how the changes are related to kidney injury was not fully analyzed. It is unclear if there are significant metabolic changes during the kidney recovery or repair phase following renal IRI. The differential changes in the metabolme of plasma, kidney cortex, and medulla are unknown
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