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Published on: July 3, 2013
Chronic NOS Inhibition Affects Oxidative State and Antioxidant Response Differently in the Kidneys of Young
M Majzunova1,2, M Kvandova3, A Berenyiova1
1Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia.
Abstract:
Deficiency of nitric oxide (NO) and oxidative stress can be a cause, a consequence, or, more often, a potentiating factor for hypertension and hypertensive renal disease. Both NO and superoxide anions are radical molecules that interact with each other, leading to oxidative damage of such organs as the kidney. In the present study, we investigated the effect of chronic-specific (neuronal NOS inhibition) and nonspecific NOS inhibition on the oxidative state and antioxidant response and associated oxidative damage of the kidney of young normotensive and hypertensive rats. Young male normotensive Wistar rats (WRs, age 4 weeks) and spontaneously hypertensive rats (SHRs, age 4 weeks) were divided into three groups for each strain by the type of administered compounds. The first group was treated with 7-nitroindazole (WR+7-NI; SHR+7-NI), the second group was treated with N(G)-nitro-L-arginine-methyl ester (WR+L-NAME; SHR+L-NAME), and the control group was treated with pure drinking water (WR; SHR) continuously for up to 6 weeks. Systolic blood pressure increased in WR+L-NAME after the first week of administration and increased slightly in SHR+L-NAME in the third week of treatment. 7-NI had no effect on blood pressure. While total NOS activity was not affected by chronic NOS inhibition in any of the WR groups, it was attenuated in SHR+7-NI and SHR+L-NAME. Nitration of proteins (3-nitrotyrosine expression) was significantly reduced in WR+7NI but not in WR+L-NAME and increased in SHR+7-NI and SHR+L-NAME. Immunoblotting analysis of SOD isoforms showed decreased SOD2 and SOD3 expressions in both WR+7-NI and WR+L-NAME followed by increased SOD activity in WR+L-NAME. Conversely, increased expression of SOD2 and SOD3 was observed in SHR+L-NAME and SHR+7-NI, respectively. SOD1 expression and total activity of SOD did not change in the SHR groups. Our results show that the antioxidant defense system plays an important role in maintaining the oxidative state during NO deficiency. While the functioning antioxidant system seeks to balance the oxidation state in the renal cortex of normotensive WRs, the impaired antioxidant activity leads to the development of oxidative damage of proteins in the kidney induced by peroxynitrite in SHRs.
Insights
Nitric oxide (NO) deficiency and oxidative stress contribute to hypertension. This study shows that while antioxidant systems balance NO deficiency in normotensive rats, impaired activity in hypertensive rats leads to kidney damage.
Area of Science:
- Nephrology
- Cardiovascular Research
- Oxidative Stress Biology
Background:
- Nitric oxide (NO) deficiency and oxidative stress are implicated in hypertension and hypertensive renal disease.
- Radical molecules like NO and superoxide anions interact, causing oxidative damage to organs, particularly the kidneys.
- Understanding the interplay between NO metabolism and antioxidant responses is crucial for managing hypertensive renal conditions.
Purpose of the Study:
- To investigate the impact of chronic neuronal and non-specific nitric oxide synthase (NOS) inhibition on the oxidative state and antioxidant response in the kidneys of normotensive and spontaneously hypertensive rats.
- To assess the resulting oxidative damage to renal tissues under conditions of NO deficiency.
- To elucidate the role of the antioxidant defense system in mitigating or exacerbating kidney damage during NO deficiency in hypertension.
Main Methods:
- Utilized young male normotensive Wistar rats (WRs) and spontaneously hypertensive rats (SHRs).
- Administered 7-nitroindazole (7-NI) or N(G)-nitro-L-arginine-methyl ester (L-NAME) to inhibit NOS, alongside a control group, for six weeks.
- Analyzed systolic blood pressure, total NOS activity, protein nitration (3-nitrotyrosine expression), and superoxide dismutase (SOD) isoform expression and activity.
Main Results:
- L-NAME increased systolic blood pressure in normotensive rats; 7-NI had no effect on blood pressure.
- Chronic NOS inhibition attenuated total NOS activity in hypertensive rats (SHR+7-NI, SHR+L-NAME).
- Protein nitration increased in hypertensive rats (SHR+7-NI, SHR+L-NAME) but decreased in normotensive rats treated with 7-NI (WR+7-NI).
- SOD2 and SOD3 expressions decreased in normotensive rats under NOS inhibition but increased in hypertensive rats.
- Antioxidant defense systems attempted to balance oxidation in normotensive rats, but impaired activity in hypertensive rats led to protein oxidative damage in the kidneys.
Conclusions:
- The antioxidant defense system is vital for maintaining oxidative balance during nitric oxide deficiency.
- In normotensive rats, a functional antioxidant system counteracts NO deficiency-induced oxidative stress.
- Impaired antioxidant activity in hypertensive rats exacerbates kidney damage, evidenced by increased protein nitration and oxidative damage.
- These findings highlight the critical role of antioxidant capacity in the pathogenesis of hypertensive renal disease.
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