No abstract

No abstract

We recently reported involvement of oxidative stress in anxiety-like behavior of rats. Others in separate studies have demonstrated a link between oxidative stress and hypertension as well as with type 2 diabetes/insulin resistance. In the present study, we have tested a putative role of oxidative stress in anxiety-like behavior, hypertension and insulin resistance using a rat model of oxidative stress. Oxidative stress in rats was produced by xanthine (0.1%; drinking water) and xanthine oxidase (5U/kg; i.p.). X+XO-treated rats had increased plasma and urinary 8-isoprostane levels (a marker of oxidative stress) and increased malondialdehyde (MDA) levels in the hippocampus and amygdala as compared to control rats. Serum corticosterone (a systemic marker of stress and anxiety) levels also increased with X+XO treatment. Moreover, anxiety-like behavior measured via open-field and light-dark exploration behavior tests significantly increased in X +XO-treated rats. Mean arterial blood pressure measured in anesthetized rats increased in X+XO-treated compared to control rats. Furthermore, plasma insulin but not glucose levels together with homeostasis model assessment (HOMA), an index of insulin resistance, were higher in X+XO-treated rats. Our studies suggest that oxidative stress is a common factor that link anxiety-like behavior, hypertension and insulin resistance in rats.

Previously, we have published that pharmacological induction of oxidative stress causes anxiety-like behavior in rats and also is associated with hypertension in these animals. Here, we report that sub-chronic induction of oxidative stress via pharmacological induction leads to i) reduction in glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 expression; ii) calpain mediated reduction of brain derived neurotrophic factor (BDNF) levels; iii) NFκB mediated upregulation of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α and elevated angiotensin (AT)-1 receptor levels in hippocampus, amygdala and locus coeruleus regions of the brain. Acute oxidative stress has opposite effects. We speculate that regulation of GLO1, GSR1, BDNF, NFκB and AT-1 receptor may contribute to anxiety-like behavior and hypertension in rats.

Activation of renal dopamine D1 (D1R) and angiotensin II type 1 receptors (AT 1 Rs) influences the activity of proximal tubular sodium transporter Na,K-ATPase and maintains sodium homeostasis and blood pressure. We reported recently that diminished D1R and exaggerated AT 1 R functions are associated with hypertension in old Fischer 344 × Brown Norway F1 (FBN) rats, and oxidative stress plays a central role in this phenomenon. Here we studied the mechanisms of age-associated increase in oxidative stress on diminished D1R and exaggerated AT 1 R functions in the renal proximal tubules of control and antioxidant Tempol-treated adult and old FBN rats. Although D1R numbers and D1R agonist SKF38393-mediated stimulation of [ 35 S]-GTPγS binding (index of D1R activation) were lower, G protein–coupled receptor kinase 4 (kinase that uncouples D1R) levels were higher in old FBN rats. Tempol treatment restored D1R numbers and G protein coupling and reduced G protein–coupled receptor kinase 4 levels in old FBN rats. Angiotensin II–mediated stimulation of [ 35 S]-GTPγS binding and Na,K-ATPase activity were higher in old FBN rats, which were also restored with Tempol treatment. We also measured renal AT 1 R function in adult and old Fischer 344 (F344) rats, which, despite exhibiting an age-related increase in oxidative stress and diminished renal D1R function, are normotensive. We found that diuretic and natriuretic responses to candesartan (indices of AT 1 R function) were similar in F344 rats, a likely explanation for the absence of age-associated hypertension in these rats. Perhaps, alterations in both D1R (diminished) and AT 1 R (exaggerated) functions are necessary for the development of age-associated hypertension, as seen in old FBN rats.