Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson's disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.
The hyperglycemia triggers several chronic diabetic complications mediated by increased oxidative stress that eventually causes diabetic nephropathy. The aim of this study was to examine if the sodium-glucose cotransporter (SGLT2) inhibition prevents the oxidative stress in the kidney of diabetic rats. Methods. The diabetic rat model was established by intraperitoneal injection of streptozotocin (50 mg/kg). The inhibition of SGLT2 was induced by daily subcutaneous administration of phlorizin (0.4 g/kg). Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities and by immunohistochemical analysis of 3-nitrotyrosine (3-NT). Results. Streptozotocin-induced diabetes caused hyperglycemia and lower body weight. The CAT activity decreased in cortex and medulla from diabetic rats; in contrast, the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The inhibition of SGLT2 decreased hyperglycemia. However, significant diuresis and glucosuria remain in diabetic rats. The phlorizin treatment restores the CAT and GPX activities and decreases 3-NT staining. Conclusion. The inhibition of SGLT2 by phlorizin prevents the hyperglycemia and oxidative stress in kidney of diabetic rats, suggesting a prooxidative mechanism related to SGLT2 activity.
(ANG) II can be associated with gene expression regulation. Thus we studied the possible role of ANG II in the regulation of AT 2 mRNA and protein expression. We utilized sham-operated renal ablation rats as well as renal ablation rats pretreated during the first 7 days of the development of renal damage with either the angiotensin-converting inhibitor ramipril, the AT 1 receptor antagonist losartan, or the AT2 receptor antagonist PD-123319. Renal tissue was analyzed for histological changes and expression of AT 2 receptor mRNA (by RT-PCR) and protein (by immunohistochemistry). To explore the physiological role of AT 2 receptor overexpression in the development of renal damage, blood pressure, urinary protein excretion, and renal damage were evaluated. A time-dependent increase in the expression of AT 2 receptor mRNA and protein was observed at 7, 15, and 30 days after renal ablation. Because these effects were already evident at day 7, the effects of ramipril, losartan, or PD-123319 were tested at this time. The ramipril group and the PD-123319-pretreated group showed inhibition of AT 2 receptor expression, whereas the losartan-pretreated group showed a further increase in AT 2 receptor expression. Inhibition of the AT2 receptor during renal ablation was associated with increased renal damage and a further increase in the blood pressure. This suggests that overexpression of AT 2 receptors after renal ablation is modulated by ANG II through its own AT 2 receptor and that functional expression of this effect may represent a counterregulatory mechanism to modulate the renal damage induced by renal ablation.AT 1 receptor; renovascular hypertension; losartan; PD-123319 ANGIOTENSIN (ANG) II plays an important role in the pathophysiology of renovascular hypertension through vasoconstriction of the peripheral vasculature, hypertrophy, and hyperplasia of cardiovascular cells (7,8). ANG type 1 (AT 1 ) and type 2 (AT 2 ) isoforms of the ANG II receptors have been described (9). However, expression of AT 2 receptors is high in fetal tissues but decreases during development (20). Expression of AT 2 receptors in the adult can be upregulated in cardiovascular diseases such as ischemia and myocardial postinfarct (15). Hence, expression of AT 2 receptors during the development of pathophysiological conditions may be relevant for the fate of the disease. Indeed, we (1) recently demonstrated an induction of the expression of AT 2 receptor mRNA, associated with an increased renal vasodilatation in hypertensive rats (1), suggesting that overexpression of AT 2 receptors might represent a counterregulatory mechanism of the prohypertensive effects induced by ANG II (1). This hypothesis is supported by other studies (4, 10, 15, 16) demonstrating 1) pressor hypersensitivity to ANG II in mice lacking the AT 2 receptor; and 2) prevention of the hypotensive response to AT 1 receptor blockade by selective antagonism of AT 2 receptors in a renal wrap hypertension model. Elevated concentrations of ANG II can be found in some of the pathologie...
The present study evaluated whether enalaprilat (the active form of enalapril, an angiotensin-converting enzyme inhibitor) activates B1 receptors. We observed that the levels of B1 receptor mRNA and protein expression were upregulated in the kidneys of diabetic rats. Bradykinin (BK)-induced renal vasodilation decreased in isolated perfused kidneys of diabetic rats, but des-Arg9-BK-induced renal vasodilation increased. Enalaprilat also produced vasodilation in the isolated perfused kidneys of control and diabetic rats. The response to des-Arg9-BK or enalaprilat was blocked by Lys-(des-Arg9, Leu8)-BK (a B1 receptor antagonist) and N-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase). These results suggest that enalaprilat activates B1 receptors and stimulates the production of nitric oxide in the kidneys of both control and diabetic rats.
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