Age-related alterations of oxidative stress and arginase activity as a response to intestinal ischemia-reperfusion in rat kidney and liver

Abstract

THE AGING PROCESS is a multifactorial biological phenomenon that is characterized by the loss of adaptive responses to conditions of physiological stress, resulting in an increased susceptibility to disease and death. Although there is considerable evidence that aging occurs as a consequence of oxidative stress, the results in animals and humans are still contradictory. Nevertheless, reactive oxygen species (ROS) produced during cellular metabolism lead to an age-dependent increase in oxidatively modified proteins, lipids, and nucleic acids in tissues. Intestinal ischemia-reperfusion (I/R) injury is a serious disorder, primarily seen in the elderly population which causes damage to various organs leading to multiple-organ dysfunction syndrome. As with the aging process, ROS are involved in the I/R injury. During an ischemic period adenosine triphosphate (ATP) production diminishes and ATP degradation causes accumulation of hypoxanthine oxidase in the cell. Conversion of xanthine dehydrogenase to xanthine oxidase in the early phase of ischemia is followed by the availability of oxygen in the reperfusion period by the conversion of hypoxanthine to xanthine with subsequent production of superoxide ions. Superoxide ions are further converted to other forms of ROS. It is known that superoxide ions react with nitric oxide (NO) to produce peroxynitrite (OONO ), which then causes enhanced lipid peroxidation, DNA, and protein modifications resulting in cellular damage. The contribution of NO and OONO to the pathogenesis of I/R injury has been studied extensively. Besides its beneficial effects as a vasodilator and an antiaggregating agent; NO also has deleterious effects on cells by both direct cytotoxic effect(s) and by indirect actions from generating OONO . NO is synthesized from arginine by nitric oxide synthase (NOS) with neuronal NOS, endothelial NOS, and inducible NOS forms. NO production, therefore, is modulated by the availability, recycling, and degradation of intracellular arginine. Arginine serves as a common substrate for both NOS and arginase. Arginase, which is an enzyme of the urea cycle in the liver (type I, liver type), is also expressed in extrahepatic tissues (type II, kidney type). Extrahepatic arginase induction is mainly responsible for downregulating NO production by consuming arginine. Therefore, arginase may contribute to oxidative stress occurring during I/R injury by regulating NO levels. In our previous study, decreased arginase activity (together with enhanced lipid peroxidation and glutathione [GSH]-depletion) has been investigated in rat renal tissues following intestinal I/R. The present study was performed to determine the effect of aging on arginase activity, on generation of malondialdehyde (MDA), a lipid peroxidation product, and on GSH levels in rat kidney and liver in response to intestinal I/R injury.