Effects of tempol on renal angiotensinogen production in Dahl salt-sensitive rats

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Abstract

We have recently reported that Dahl salt-sensitive rats (DS) on high salt diet (HS) have an inappropriate augmentation of intrarenal angiotensinogen. Recent studies also reported that the augmented superoxide anion formation plays important roles in this animal model of hypertension. This study was performed to address the hypothesis that an inappropriate augmentation of intrarenal angiotensinogen by HS is caused by the augmented reactive oxygen species. Male DS (200–220 g) were maintained on low salt diet LS (N=7) or HS (N=27) for 4 weeks. The HS group was subdivided into three subgroups to receive null (N=12), superoxide dismutase mimetic, tempol (3 mmol/l, N=8), or vasodilator, hydralazine (0.5 mmol/l, N=7) in drinking water during the period. Systolic BP was significantly increased in the DS + HS group compared to the DS + LS group (184 ± 7 mmHg vs. 107 ± 5 at 4-week). Tempol or hydralazine treatment equivalently attenuated the hypertension (128 ± 3 and 127 ± 5 at 4-week, respectively). Urinary excretion of thiobarbituric acid reactive substances at 4-week was significantly increased in the DS + HS group compared to the DS + LS group (0.66 ± 0.05 μmol/day vs. 0.14 ± 0.01). Tempol treatment prevented this effect (0.24 ± 0.04) but hydralazine treatment only partially prevented the effect (0.40 ± 0.03). Kidney angiotensinogen levels, measured by Western blot analysis, were significantly increased in the DS + HS group compared to the DS + LS group (32 ± 5 densitometric units vs. 21 ± 1). Tempol (14 ± 3) but not hydralazine (32 ± 5) treatment prevented the intrarenal angiotensinogen augmentation. The evidence suggests that the enhanced intrarenal angiotensinogen in DS challenged with HS is associated with the augmented reactive oxygen species.

Section snippets

Materials and methods

The experimental protocol was approved by the Animal Care and Use Committees at Tulane University and Kagawa University. Male DS (200–220 g, Seac Yoshitomi, Fukuoka, Japan, N=34) were selected at random to receive HS (8% NaCl, Oriental Yeast, Osaka, Japan, N=27) or low salt diet (LS, 0.3% NaCl, Oriental Yeast, N=7) for 4 weeks. The HS group was subdivided into three subgroups to receive null (N=12), superoxide dismutase mimetic, tempol (T, 3 mmol/l, N=8, Sigma, Missouri, USA), or vasodilator,

Results

Temporal profile of systolic BP is depicted in Fig. 1A. Systolic BP levels were similar among the four groups at the beginning of protocol. Systolic BP was significantly increased in the DS + HS group compared to the DS + LS group (184 ± 7 mmHg vs. 107 ± 5 at 4-week). Tempol or hydralazine treatment equivalently attenuated the hypertension (128 ± 3 and 127 ± 5 at 4-week, respectively).

Plasma AGT levels are depicted in Fig. 2A. HS significantly suppressed plasma AGT levels. Tempol or hydralazine treatment

Discussion

While we recently reported that DS on HS have an inappropriate augmentation of intrarenal AGT and a failure to suppress intrarenal Ang II which may contribute to the development of hypertension in this strain [9], the mechanisms responsible for an inappropriate augmentation of intrarenal AGT by HS remain incompletely understood. Meanwhile, other groups recently reported that an augmented superoxide anion formation plays an important role in this animal model of hypertension [10], [11]. These

Acknowledgements

This work was supported by grants from the Institutional Development Award Program of the National Center for Research Resources, National Institute of Health (P20RR017659, H.K.), the Ministry of Education, Science and Culture of Japan (A.N.), and the Mitsui Life Social Welfare Foundation (Tokyo, Japan, A.N.). The polyclonal antibody against rat AGT was generously provided by Dr. Conrad Sernia (University of Queensland, Australia). The authors thank Dr. L. Gabriel Navar (Tulane University) for

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