Abstract
Nitric oxide (NO) influences renal blood flow mainly as a result of neuronal nitric oxide synthase (nNOS). Nevertheless, it is unclear how nNOS expression is modulated by endogenous angiotensin II, an inhibitor of NO function. We tested the hypothesis that the angiotensin II AT1 receptor and oxidative stress mediated by NADPH oxidase contribute to the modulation of renal nNOS expression in two-kidney, one-clip (2K1C) hypertensive rats. Experiments were performed on male Wistar rats (150 to 170 g body weight) divided into 2K1C (N = 19) and sham-operated (N = 19) groups. nNOS expression in kidneys of 2K1C hypertensive rats (N = 9) was compared by Western blotting to that of 2K1C rats treated with low doses of the AT1 antagonist losartan [10 mg x kg(-1) x day(-1); N = 5] or the superoxide scavenger tempol [0.2 mmol x kg(-1) x day(-1); N = 5], which still remain hypertensive. After 28 days, nNOS expression was significantly increased by 1.7-fold in the clipped kidneys of 2K1C rats and by 3-fold in the non-clipped kidneys of 2K1C rats compared with sham rats, but was normalized by losartan. With tempol treatment, nNOS expression increased 2-fold in the clipped kidneys and 1.4-fold in the non-clipped kidneys compared with sham rats. The changes in nNOS expression were not followed by changes in the enzyme activity, as measured indirectly by the cGMP method. In conclusion, AT1 receptors and oxidative stress seem to be primary stimuli for increased nNOS expression, but this up-regulation does not result in higher enzyme activity.
Highlights
The renin-angiotensin system plays a pivotal role in the development and maintenance of two-kidney, one clip (2K1C) Goldblatt hypertension [1,2]
Selective chronic inhibition of this isoform leads to arterial hypertension and to a transient sensitization of tubuloglomerular feedback, indicating a modulatory role of nitric oxide (NO) derived from macula densa cells on arteriolar tone and tubuloglomerular feedback [10]. neuronal nitric oxide synthase (nNOS) seems to be important in counteracting angiotensin II (Ang II)-induced decreases in glomerular filtration rate via the modulation of tubuloglomerular feedback–mediated afferent arteriolar constriction and an important influence on efferent arteriolar tone [11,12]
Our data indicate that AT1 receptors and oxidative stress could be primary stimuli for the increased nNOS expression, the enzyme activity seems to be diminished, as indirectly indicated by cyclic GMP (cGMP) quantitation
Summary
The renin-angiotensin system plays a pivotal role in the development and maintenance of two-kidney, one clip (2K1C) Goldblatt hypertension [1,2]. NO is one of the best vasorelaxant autocoids which, in addition to exerting systemic control of blood pressure [4], exerts a paracrine control of the microvascular tone in the kidney [5]. Both acute and chronic inhibition of NO results in a significant increase in renal vascular resistance, confirming its role in the modulation of renal blood flow [6,7,8]. Selective chronic inhibition of this isoform leads to arterial hypertension and to a transient sensitization of tubuloglomerular feedback, indicating a modulatory role of NO derived from macula densa cells on arteriolar tone and tubuloglomerular feedback [10]. nNOS seems to be important in counteracting Ang II-induced decreases in glomerular filtration rate via the modulation of tubuloglomerular feedback–mediated afferent arteriolar constriction and an important influence on efferent arteriolar tone [11,12]
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