Antioxidant status, lipid peroxidation and nitric oxide end products in patients of type 2 diabetes mellitus with nephropathy
Introduction
Diabetic nephropathy, a preeminent cause of end stage renal disease is associated with much morbidity and mortality due to renal failure and also due to an increased risk of cardiovascular disease [1]. High intracellular glucose concentration has been suggested to be a prerequisite for development of structural and functional changes in the kidney typical of diabetic nephropathy. Many biochemical pathways that are promoted in hyperglycemic state, for example, glucose autoxidation, polyol pathway, prostanoid synthesis and protein glycation can increase the production of free radicals [2]. The term reactive oxygen species (ROS) includes both oxygen radicals such as superoxide (O2−•), alkoxyl (RO·), peroxyl (ROO•) and hydroxyl (OH•) radicals, plus nonradical derivatives of oxygen, namely hydrogen peroxide (H2O2). Reactive oxygen species are continuously generated in physiologic conditions and effectively eliminated by several intracellular and extracellular antioxidative systems [3]. When the generation of ROS exceeds cellular defense mechanisms, these unstable molecules interact with biologic macromolecules such as lipids, proteins and DNA and lead to structural changes as well as functional abnormalities.
Oxidative stress has been considered to be a common pathogenic factor in DM and its complications [4] including nephropathy [5], [6]. In diabetic nephropathy, free radicals have been shown to decrease de novo synthesis of heparan sulfate proteoglycans, which correlates with proteinuria seen in this condition [7]. Production of advanced glycation end products (AGEs) in DM and their interaction with receptors is a potential source of free radicals and can induce renal injury [8]. Altered generation and metabolism of nitric oxide has been proposed as one of the causes of vascular dysfunction and development of diabetic nephropathy [9]. Nitric oxide is a potent vasodilator and cytostatic agent and may therefore be involved in diabetic angiopathies. Following radical-radical interaction with superoxide, NO produces another potent oxidant, the peroxynitrite anion, which rapidly decomposes to give significant quantities of hydroxyl radical, nitrate and nitrite [10]. Peroxynitrite by itself is also a potent oxidant. Thus, in biologic systems where cogeneration of multiple reactive species occurs, a complex interaction exists between NO and ROS [11].
A number of studies have evaluated the role of oxidative stress in diabetes and its complications but with inconsistent results. While some authors reported increased oxidative damage (measured as levels of MDA or lipid peroxides) and lowered antioxidant defenses (measured as activities of antioxidant enzymes, vitamin E or C or as total radical trapping antioxidant parameter) in patients of DM with [12], [13], [14], [15] and without complications [16], [17], [18], [19], [20], others have reported no change in indices of oxidative stress [21], [22]. Similarly, either increased [23], [24] or decreased [25] levels of nitric oxide end products have been reported in patients of DM. Data on oxidative stress in patients of type 2 DM with nephropathy is scant especially in patients of Asian Indian ethnic origin. The present study was undertaken to assess lipid peroxidation, antioxidant status and NO production in type 2 diabetic patients with nephropathy.
Section snippets
Subjects
Study was conducted in 60 type 2 diabetic patients attending medical outpatient department and diabetic clinic in G. T. B. hospital. Diagnosis of DM was made according to revised American Diabetes Association criteria [26]. Patients with age above 30 years and minimum of one-year duration of diabetes were included. Patients with any renal dysfunction (i.e. raised blood urea and serum creatinine levels), with coexistent illness (i.e. infections), congestive heart failure, acute myocardial
Results
Clinical characteristics of patients and controls are summarized in Table 1. All the subjects were matched for age, sex and BMI. Glycemic control and duration of diabetes mellitus were similar in both the patient groups. Blood urea, serum creatinine and uric acid concentration was within the normal reference range in all the three study groups.
As compared to controls, serum MDA concentration was significantly higher in patients of type 2 DM both with (p < 0.05) and without nephropathy (p <
Discussion
Oxidative stress is considered to be the unifying link between diabetes mellitus and its complications. Data on oxidative stress in patients of type 2 diabetes mellitus with nephropathy is scant. Our study evaluates oxidative stress and NO pathways in patients of type 2 diabetes mellitus with nephropathy in Asian Indian ethnic population. We have found significantly higher serum MDA level in type 2 diabetic patients, which is in agreement with many previously reported studies [12], [15], [20],
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