Hepatic nitrosative stress in experimental diabetes☆
Introduction
The excessive formation of free radicals in many reactions plays a crucial role in the pathogenesis of chronic diabetic complications (Bonnefont-Rousselot, 2002, Ceriello, 2003). The enhanced level of metabolism in mitochondria leads to increased leakage of superoxide (O2−·) from the respiratory chain; furthermore, inducible nitric oxide synthase (iNOS) is induced by many factors, resulting in the production of excess nitric oxide (NO) and O2−· (Ha & Lee, 2000, Nishikawa et al., 2000, Pacher et al., 2007). The interaction of the diffusing NO with the O2 −· results in the formation of peroxynitrite (ONOO −) at a diffusion-coefficient-limited rate. Nitrosative stress occurs when the production of the highly reactive nitrogen-containing chemicals exceeds the ability of the human body to neutralize and eliminate them. Nitrosative stress can lead to reactions that alter protein structure, interfering with normal body functions. Oxidative stress causes increased expression of transcription factors that favor increased expression of iNOS and nitrosative stress (Di Naso et al., 2011, Dias et al., 2005). Notably, transcription factors, such as NF-κB, have an important role in the pathogenesis of diabetic complications, and p65 overexpression in the nucleus is related to this activation process.
The liver, which is rich in mitochondria, is an organ that is important to both energy and substance metabolism. Therefore, damage to the liver mitochondria will aggravate the metabolic disorders in diabetes. The liver is the main organ of oxidative and detoxifying processes, as well as free radical reactions. In many diseases, the biomarkers of oxidative stress are elevated in the liver at an early stage (Dey & Swaminathan, 2010, Ren et al., 2011).
Aminoguanidine (AG) is a prototype therapeutic agent for the prevention of advanced glycation end product (AGE) formation. AG reacts rapidly with a,b-dicarbonyl compounds, such as methylglyoxal, glyoxal, and 3-deoxyglucosone, to prevent the formation of AGEs (Thornalley, 2003). The adducts formed are substituted derivatives of 3-amino-1,2,4-triazine. The inhibition of disease mechanisms, particularly vascular complications in experimental diabetes, via AG demonstrates that the accumulation of AGEs is a risk factor for disease progression (Degenhardt et al., 1999). In addition to the effects on advanced glycation, aminoguanidine at low dose can act in a specific manner via the inhibition of nitric oxide synthase (iNOS) activity and nitrosative stress reduction (Szabo et al., 1997). Additionally, AG can inhibit the metabolism of histamine, the catabolism of polyamines and the activity of catalase, and increase the effects of angiotensin in the production of prostacyclin (Nilsson, 1999). Although many inhibitors of NO synthase have been developed to date, few selective inhibitors for the individual isoforms of NOS (inducible, endothelial, neuronal) have been described. Among these, AG has been identified as one of the first iNOS-selective inhibitors (Pacher et al., 2007) (Fig. 1).
Because the liver is subjected to ROS-mediated injury in diabetes, our experiments were performed to investigate the potential protective effects of aminoguanidine treatment on liver oxidative and nitrosative stress in an experimental model of diabetes mellitus.
Section snippets
Animals and experimental protocol
The experimental protocol followed that established by the Ethical Research Committee of Health of the Research and Postgraduate Group of the Hospital de Clínicas of Porto Alegre, as well as the recommendations of the Principles for Research Involving Animals (NAS). Twenty-one male Wistar rats, obtained from the breeding colony of the Basic Health Sciences Institute of the Federal University of Rio Grande do Sul (UFRGS), were used. The animals' mean weight was 200–300 g at the beginning of the
Results
Aminoguanidine administration failed to reduce glycemia in diabetic rats. There was a significant decrease in animal weight in the DM group, and AG treatment (DM + AG) did not reverse this condition (Table 1).The DM group showed a significant increase in liver lipoperoxidation (0.46 ± 0.11 vs 1.10 ± 0.06 nmol/mg protein; p < 0.05), and treatment with AG significantly reduced these values (0.50 ± 0.35 nmol/mg protein; p < 0.05) (Table 1).
iNOS expression was increased in the DM group compared with the CO
Discussion
The results of the present study confirmed previous studies describing increased liver oxidative and nitrosative stress in a model of experimental diabetes mellitus (Dias et al., 2005). Because the liver is rich in mitochondria for metabolic functions, it is a crucially important organ, and in a chronic hyperglycemic state, liver oxidative stress is considered a relevant process (Ren, Li, Qi, & Niu, 2008).
Aminoguanidine administration did not affect the glycemic values of the diabetic animals.
Acknowledgments
This work was supported by grants from the Brazilian Agencies “Fundo de Incentivo à Pesquisa e Eventos (FIPE) do Hospital de Clínicas de Porto Alegre (HCPA)”, and “Laboratório de Hepatologia e Fisiologia Experimental da Universidade Federal do Rio Grande do Sul (HCPA/UFRGS)”.
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Conflicts of interest: None.