Chronic NOS Inhibition Affects Oxidative State and Antioxidant Response Differently in the Kidneys of Young Normotensive and Hypertensive Rats

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.

Prolonged Diuretic and Renoprotective Effects of a Xanthone Obtained from Garcinia achachairu Rusby in Normotensive and Hypertensive Rats

“…NO is involved in several physiological processes in the kidneys, including diuresis and natriuresis [36]. Our kidney sample results reveal no differences in the nitrite content between the SHR and NTR treated with VEH only, a result similar to that found by Almeida et al [28].…”

Role of hydrogen sulfide in endothelial dysfunction: Pathophysiology and therapeutic approaches

“…The NO-deficiency impairs vascular homeostasis, alters the endothelium permeability and consequently leads to inflammatory and fibrotic processes, which are responsible for structural alterations, including vascular hypertrophy and increased vascular resistances. Consistently, chronic administration of NOS inhibitors causes sustained hypertension in several pre-clinical models [20] , [21] .…”

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease

“…Protein nitration was increased in the renal cortex of SHRs treated with the NOS inhibitor, L-NAME ( Majzunova et al, 2019 ). Renal expression of Mn-SOD was increased in SHR in response to treatment with L-NAME, although total SOD activity remained unchanged ( Majzunova et al, 2019 ).…”

“…Protein nitration was increased in the renal cortex of SHRs treated with the NOS inhibitor, L-NAME ( Majzunova et al, 2019 ). Renal expression of Mn-SOD was increased in SHR in response to treatment with L-NAME, although total SOD activity remained unchanged ( Majzunova et al, 2019 ). These data suggest that the impaired antioxidant response combined with a deficiency in NO may promote oxidative damage of proteins in the kidney via the production of ONOO – in SHRs.…”