Abstract
Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week meldonium pre-treatment (300 mg/kg b.m./day) on acute renal I/R in male rats (Wistar strain). Our results showed that meldonium decreased animal body mass gain, food and water intake, and carnitine, glucose, and lactic acid kidney content. In kidneys of animals subjected to I/R, meldonium increased phosphorylation of mitogen-activated protein kinase p38 and protein kinase B, and increased the expression of nuclear factor erythroid 2-related factor 2 and haeme oxygenase 1, causing manganese superoxide dismutase expression and activity to increase, as well as lipid peroxidation, cooper-zinc superoxide dismutase, glutathione peroxidase, and glutathione reductase activities to decrease. By decreasing the kidney Bax/Bcl2 expression ratio and kidney and serum high mobility group box 1 protein content, meldonium reduced apoptotic and necrotic events in I/R, as confirmed by kidney histology. Meldonium increased adrenal noradrenaline content and serum, adrenal, hepatic, and renal ascorbic/dehydroascorbic acid ratio, which caused complex changes in renal lipidomics. Taken together, our results have confirmed that meldonium pre-treatment protects against I/R-induced oxidative stress and apoptosis/necrosis.
Highlights
Acute renal ischemia/reperfusion (I/R) is a temporary restriction of kidney blood supply, followed by blood flow restoration and re-oxygenation
Meldonium decreases the risk of a long-chain fatty acid and metabolism mediated mitochondrial injury, shifting energy production from fatty acids oxidation to less oxygen-demanding glycolysis, which is more favorable under ischemic conditions
Our measurement of body mass and food and water intake were completed before the surgical procedures, meaning that all detected changes were caused by meldonium and not by surgical procedures
Summary
Acute renal ischemia/reperfusion (I/R) is a temporary restriction of kidney blood supply, followed by blood flow restoration and re-oxygenation. Meldonium is an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia [6]. Long-chain fatty acids are metabolized to medium- and short-chain acyl carnitines for further oxidation in mitochondria, which prevents the mitochondrial accumulation of toxic long-chain intermediates [8]. In this way, meldonium decreases the risk of a long-chain fatty acid and metabolism mediated mitochondrial injury, shifting energy production from fatty acids oxidation to less oxygen-demanding glycolysis, which is more favorable under ischemic conditions
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