This Article Abstract Full Text (PDF) All Versions of this Article: 41/2/341    most recent 01.HYP.0000052833.20759.64v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rodriguez-Iturbe, B. Articles by Vaziri, N. D. Search for Related Content PubMed PubMed Citation Articles by Rodriguez-Iturbe, B. Articles by Vaziri, N. D. Related Collections Other hypertension

(Hypertension. 2003;41:341.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Antioxidant-Rich Diet Relieves Hypertension and Reduces Renal Immune Infiltration in Spontaneously Hypertensive Rats

Bernardo Rodriguez-Iturbe; Chang-De Zhan; Yasmir Quiroz; Ram K. Sindhu; Nosratola D. Vaziri

From Renal Service and Laboratory, Hospital Universitario, Instituto de Investigaciones Biomédicas (Fundacite-Zulia), Universidad del Zulia (B.R.-I., Y.Q.), Maracaibo, Venezuela; and the Division of Nephrology and Hypertension, Department of Medicine, Physiology and Biophysics, University of California (C.-D.Z., R.K.S., N.D.V.), Irvine.

Correspondence to Dr Bernardo Rodríguez-Iturbe, Renal Service and Laboratory, Hospital Universitario, Instituto de Investigaciones Biomédicas (Fundacite-Zulia), Universidad del Zulia, Maracaibo, Venezuela. E-mail bri{at}iamnet.com

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Previous studies have demonstrated that oxidative stress contributes to hypertension and treatments with either antioxidant or immunosuppressive/anti-inflammatory agents improve hypertension in spontaneously hypertensive rats (SHR). The present study was performed to determine if the antihypertensive effects of an antioxidant-rich diet are associated with reduction in the renal immune infiltration. Rats were divided into experimental groups (n=5 each) that were followed 7 months after birth, during which they were fed either a regular or antioxidant-enriched (test) diet as follows: SHR-R group=regular diet; SHR-T group=test diet throughout the experiment; SHR-S group=test diet for 4 months switched to regular diet thereafter; WKY group=control rats given regular diet. The SHR-T rats showed a significant reduction in systolic blood pressure (mm Hg): SHR-T=179.6±12.9 versus SHR-R=207.5±9.6 (P<0.001) and plasma hydrogen peroxide concentration (SHR-T=15±4 µmol/L versus 34±9 in SHR-R rats). This was accompanied by significant reductions of renal tissue nitrotyrosine abundance, tubulointerstitial infiltration (cells/mm²) of lymphocytes (SHR-T=18±3 versus SHR-R=30±4, P<0.001), macrophages (SHR-T= 17±3 versus SHR-R=22±3), and angiotensin II–positive cells (SHR-T= 17±2 versus SHR-R=25±5, P<0.01). Results in the SHR-S group were intermediate between the SHR-R and SHR-T groups. The intensity of the infiltration of lymphocytes, macrophages, and angiotensin II–positive cells significantly correlated with systolic blood pressure. Thus, the present study demonstrates that an antioxidant-enriched diet reduces the renal interstitial inflammation and improves hypertension in SHR. These findings point to interrelation between oxidative stress and inflammatory reactivity in the pathogenesis of hypertension.

Key Words: antioxidants • lymphocytes • macrophages • immune systems • kidney • rats, spontaneously hypertensive

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Evidence supporting the role of oxidative stress in the pathogenesis of hypertension has been advanced in recent years.^1–4 The most compelling studies demonstrate that hypertension may, in part, develop as a result of increased reactive oxygen species^5–11 and that a variety of antioxidant therapies ameliorate hypertension in rats with genetic and acquired forms of hypertension.^12–23

Hypertensive effects of oxidative stress are the consequence, at least in part, of endothelial dysfunction resulting from disturbances of vasodilator systems, particularly degradation of nitric oxide by oxygen free radicals.^24–26 In addition, oxidative stress in the kidney may be involved in the pathogenesis of salt retention. We have postulated that renal infiltration of immunocompetent cells may play a role in the pathogenesis of salt-sensitive hypertension.^27,28 Tubulointerstitial infiltration of lymphocytes and macrophages is associated with the generation of reactive oxygen species (ROS) and angiotensin II–producing cells in experimental models of hypertension.^29–32 As a consequence, increased sodium reabsorption, impaired pressure natriuresis, and decreased filtered sodium caused by glomerular vasoconstriction may develop,³³ imposing a pathophysiological state that favors sodium retention (reviewed by Johnson et al³⁴).

Previous studies from our group have shown that reduction of the immune infiltration with an immunosuppressive drug, mycophenolate mofetil, improves oxidative stress as well as hypertension.^29–32 The present investigations examine the opposite side of the same issue: whether the long-term administration of an antioxidant-rich diet would reduce the renal immune infiltration as well as improve systemic hypertension.

Our findings indicate that an antioxidant-rich diet ameliorates hypertension in spontaneously hypertensive rats (SHR) in association with reduction in the infiltration of lymphocytes and macrophages in tubulointerstitial areas of the kidney.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Animals and Experimental Design
Experiments were done in SHR and control Wistar-Kyoto rats (WKY) obtained from Charles River Laboratories. One-week–pregnant rats and their offspring were fed either a regular rodent laboratory diet or a test diet prepared by adding to the regular diet vitamin E, vitamin C, zinc, and selenium. Diets were purchased from Purina Mills Inc. The differences in the composition of the regular diet and the test diet are shown in the Table. The male offspring were observed for 7 months

View this table: [in this window] [in a new window]   Vitamin E, Vitamin C, Zinc, and Selenium Contents of Regular and Test Diets*

Animals were housed in a temperature-controlled light-regulated space with 12-hour light and dark cycles and were given unrestricted access to food and water throughout the experiments. The protocol used in this study was approved by the animal care and use committee of the University of California, Irvine.

The pregnant animals and their offspring were randomly assigned to the following experimental groups (n=5 each): SHR-R group, consisting of SHR rats that were given regular diet throughout the experiment (7 months); SHR-T group, consisting of SHR rats that were given test (antioxidant-rich) diet throughout the experiment; SHR-S group, consisting on rats that received test diet for 4 months and then were switched to a regular diet for the remaining 3 months; and the WKY group, consisting of WKY rats given a regular diet throughout the experiments.

At the end of the experiments, animals were euthanized after being anesthetized with intraperitoneal injections of pentobarbital sodium (Nembutal, 50 mg/kg). Blood was obtained and kidneys were removed. One kidney was used for histological and immunohistological studies and the other kidney was used to determine malondialdehyde (MDA) content.

Serum and urine creatinine was determined by a kit purchased from Sigma Chemical Inc. Urinary protein and creatinine concentrations were determined in the 24-hour urine collections.

Plasma Hydrogen Peroxide
Plasma H₂O₂ concentration was determined by the quantitative H₂O₂ assay kit (OXIS International Inc). Nitrotyrosine abundance in renal tissue was determined by Western blot analysis as described in our earlier studies.⁹

Blood Pressure Determinations
Blood pressure was determined by tail-cuff plethysmography, as described previously.³⁵ Conscious rats were placed on a heated pad in a temperature-controlled quiet room. After 15 minutes of rest with the tail placed inside a tail cuff, the cuff was inflated 3 to 4 times to condition the animal to the procedure; 4 consecutive measurements were taken and recorded (Harvard Apparatus Inc).

Histology
Coronal 3- to 4-µm sections of paraffin-embedded tissue fixed in 10% buffered formalin (American Master*Tech Scientific, Inc) were used for histological studies. Periodic acid-Schiff (PAS), trichromic, and hematoxylin and eosin staining were used to evaluate light microscopic findings. The entire cortical and juxtamedullary regions were examined. Glomerulosclerosis was defined as PAS-stained material without cellular elements with or without adhesion to Bowman’s capsule. Glomerulosclerosis was graded by the score described by Raij³⁶ and detailed in previous communications.³⁰ Tubulointerstitial damage was classified according to the extent (%) of areas of tubular damage by a scale ranging from 0 to 5+, described previously^30–32: 0=no changes present; 1+=<10%; 2+=10% to 25%; 3+=25% to 50%; 4+=50% to 75%; 5+=75% to 100%. All histological studies were done in a blinded manner.

Cellular Infiltration
Lymphocytes (CD5-positive cells) and macrophages (ED1-positive cells) were identified by avidin-biotin-peroxidase methodology. Angiotensin II–positive cells were identified by indirect immunofluorescence. Cellular counts within the glomeruli are given as positive cells per glomerular cross section (gcs) and in tubulointerstitial areas as positive cells per millimeter².^29–32

Antisera
Lymphocytes were identified with anti-CD5 monoclonal antibody (clone MRCOX19, Biosource) and macrophages with anti-ED1 monoclonal antibody (Harlan Bioproducts). Angiotensin II–producing cells were investigated with rabbit anti-human angiotensin II antisera (Peninsula Laboratories) with cross-reactivity to rat angiotensin II.^29–32 Secondary rat anti-mouse and donkey anti-rabbit antibodies with minimal cross-reactivity to rat serum proteins were obtained from Accurate Chemical and Scientific Co.

Renal MDA
Renal MDA content was determined in kidney homogenates by the method of Buege and Aust.³⁷

Statistical Calculations
Comparisons between groups were done by using multiple-group ANOVA analysis. Significant differences were evaluated with Tukey-Kramer posttests. Associations between variables were explored with linear (Pearson) as well as nonparametric (Spearman) correlation coefficients. Differences were considered significant when 2-tailed tests indicated values of P<0.05. Calculations were made with the help of a commercially available statistical package (Instat, GraphPad). Results are expressed as mean±SD throughout the article.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Weight, Renal Function, Blood Pressure, and Indicators of Oxidative Stress
There were no significant differences in weight among the experimental groups and control animals. At the end of the experiment, the weights were as follows: WKY=341±27.4 g; SHR-R group=345±21.3 g; SHR-S group=322±33.9 g; SHR-T group=327±18.9 g.

Creatinine clearance (mL/min) at the end of the experiment was similar in the WKY control rats (1.23±0.27) and in rats from the SHR-R (1.03±0.2), SHR-S (1.11±0.22) and SHR-T group (1.25±0.19). Urinary protein excretion (mg/24 hours) was mildly but significantly (P<0.05) increased in all SHR groups as compared with the WKY group (SHR-R group=38.6±6.2; SHR-S group=36.9±7.4; SHR-T group=39.9±6.3; WKY group=26.9±4.9).

Mean renal MDA content (nmol/mg kidney protein) was higher in the SHR-R group (2.45±0.57) than in rats of the SHR-S group (2.25±0.37), SHR-T group (2.0±0.13), and the WKY group (2.16±0.10), but the differences were not statistically significant.

Plasma hydrogen peroxide concentration (µmol/L) in the SHR-R group (34±9) was significantly (P<0.05, ANOVA) higher than those found in the SHR-T (15±4) and WKY (18±8) groups. The SHR-S group showed an intermediate plasma hydrogen peroxide level (24±4). Renal tissue nitrotyrosine burden (an indicator of NO inactivation by ROS) was significantly increased in the SHR-R group (1977±103) compared with the WKY group (1693±81, P<0.05). It was significantly lowered by antioxidant therapy in the SHR-T group (1611±80) and was raised slightly by switching to the regular diet in the SHR-S group (1649±86). (Data represent mean±SD of relative optical densities of bands on Western analysis.) These findings point to increased ROS in the untreated SHR and the efficacy of the antioxidant diet used.

As expected, SHR of all experimental groups were hypertensive (Figure 1). Rats from the SHR-T group that received antioxidant-rich diet throughout the experiment had a significant (P<0.01) reduction of blood pressure compared with the rats of the SHR-R group that received a regular diet. (SHR-T=179.6±12,9 mm Hg versus SHR-R=207.5±9.6). The SHR-S group, in which the test diet was switched to regular during the last 3 months, had intermediate blood pressure values (198±14.8 mm Hg).

View larger version (27K): [in this window] [in a new window]   Figure 1. Systolic blood pressure at the end of the experimental period. All experimental groups had significantly (P<0.001) higher values than control WKY rats (open bar). Antioxidant-rich test diet reduced significantly (**P<0.01) the blood pressure in rats receiving the test diet (SHR-T, striped bar) with respect to rats on a regular diet (SHR-R, closed bar). Rats that were switched from test diet to regular diet (SHR-S, shaded bar) had intermediate degree of hypertension.

Cellular Infiltration
The glomeruli did not present significant infiltration of lymphocytes and macrophages. Intraglomerular lymphocytes (CD5-positive cells/gcs) were 0.2±0.27 in WKY rats and 0.25±0.29, 0.3±0.45, and 0.1±0.22 in SHR-R, SHR-S, and SHR-T, respectively. Macrophages (ED1-positive cells/gcs) were also similar in all groups (WKY=0.4±0.42, SHR-R=0.38±0.48, SHR-S=0.30±0.27, SHR-T=0.20±0.27).

In contrast, there were significant differences in the tubulointerstitial infiltration of lymphocytes and macrophages in the experimental groups. SHR rats from all groups had significantly higher numbers of CD5-positive cells than WKY rats. As shown in Figure 2, the more intense infiltration of CD5-positive cells was observed in rats kept on the regular diet (SHR-R) and the lowest number of CD5-positive cells in rats kept on the antioxidant-rich diet (SHR-T). Rats that were switched from the test diet to a regular diet (SHR-S) had intermediate values (Figure 2).

View larger version (28K): [in this window] [in a new window]   Figure 2. Tubulointerstitial infiltration of lymphocytes (CD5-positive cells) in 7-month-old SHR rats kept from birth on a regular diet (SHR-R, closed bar), rats switched from an antioxidant diet after 4 months (SHR-S, shaded bar), and rats kept on an antioxidant-rich test diet throughout (SHR-T, striped bar). *P<0.05, ***P<0.001. Error bars are SD.

Macrophage infiltration showed the same pattern, with the SHR-R group showing the highest number of ED1-positive cells. Rats switched from regular to antioxidant diet (SHR-S) had intermediate macrophage infiltration, and rats kept on the test diet (SHR-T) had the lowest number of tubulointerstitial macrophages (Figure 3).

View larger version (34K): [in this window] [in a new window]   Figure 3. Tubulointerstitial infiltration of macrophages (ED1-positive cells) in 7-month-old SHR rats kept from birth on a regular diet (SHR-R, closed bar), rats switched from an antioxidant diet after 4 months (SHR-S, shaded bar), and rats kept on an antioxidant-rich test diet throughout (SHR-T, striped bar). *P<0.05, ***P<0.001. Error bars are SD.

Similar findings were demonstrated with respect to angiotensin II–positive cells. As shown in Figure 4, antioxidant diet reduced the number of angiotensin II–producing cells. This effect was more pronounced in rats that were kept on the test diet (Figure 4).

View larger version (33K): [in this window] [in a new window]   Figure 4. Angiotensin II–positive tubulointerstitial cells in tubulointerstitium. SHR-R, SHR kept on a regular diet; SHR-S, SHR switched from an antioxidant diet to a regular diet; SHR-T, SHR kept on an antioxidant-rich test diet throughout. *P<0.05, ***P<0.001). Error bars are SD.

Histology
Light microscopy was essentially unremarkable in all groups of rats. Glomeruli were normal, with focal areas of increased cellularity. Tubulointerstitial areas showed focal areas of dilation, but trichromic and PAS staining did not show areas of fibrosis. Tubulointerstitial injury scores were similar in all experimental groups SHR-R=1.8±0.45; SHR-S=1.6±0.55; SHR-T=1.8±0.55; WKY=1.6±0.55). Representative photomicrographs showing light microscopy and immune histology are shown in Figure 5.

View larger version (45K): [in this window] [in a new window]   Figure 5. A, Glomeruli with partial collapse of the glomerular tuft and focal hypercellularity surrounded by tubules, some of which are dilated and with partial loss of epithelial cells but preserved basement membrane. Lymphocytes (CD5-positive cells) and macrophages (ED1-positive cells) infiltrating tubulointerstitial areas are shown in avidin-biotin peroxidase staining and FITC staining, respectively, in B and C. Angiotensin II–positive tubular cells and interstitial cells (peroxidase staining) are shown in D.

There were significant correlations between the systolic blood pressure levels and lymphocyte infiltration (r=0.80, P<0.0001), macrophage infiltration (r=0.877, P<0.0001), and angiotensin II–positive cells (r=0.828, P<0.0001). The correlations between SBP levels and the immune cell infiltration are shown in Figure 6.

View larger version (16K): [in this window] [in a new window]   Figure 6. Highly significant correlations between the number of lymphocytes (A, r=0.80, P<0.001), macrophages (B, r=0.87, P<0.001), and angiotensin II–positive cells (C, r=0.83, P<0.001) infiltrating renal tubulointerstitial areas and systolic blood pressure.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Long-term consumption of the antioxidant-fortified diet beginning in the prenatal period improved hypertension and ameliorated oxidative stress, as evidenced by the reductions of tissue nitrotyrosine and MDA contents as well as plasma hydrogen peroxide concentration in the SHR-T group. These findings are consistent with the results of the short-term studies carried by our group using the potent antioxidant lazaroid compound²² as well as those carried out by Schnackenberg et al¹⁴ using the superoxide dismutase mimetic agent tempol in this model. Together, these studies have provided compelling evidence for the role of oxidative stress in the pathogenesis of hypertension in SHR. Similarly, the presence of oxidative stress and its role in elevation of arterial pressure has been shown in various other forms of genetic and acquired hypertension including that seen with lead exposure,⁹ chronic renal insufficiency,¹⁰ experimental syndrome X,³⁸ salt sensitivity,³⁹ coarctation of the aorta,⁵ angiotensin infusion,⁴⁰ preeclampsia,⁴¹ and renal artery stenosis.⁴²

In the present study, we used an antioxidant cocktail that included vitamin E, vitamin C, selenium, and zinc. Earlier studies have documented the beneficial effects of vitamin E and vitamin C in ameliorating hypertension in hypertensive animals^9,10,22 and improving endothelial function in hypertensive humans.⁴³ In addition, selenium (the critical constituent of the antioxidant enzyme glutathione peroxidase) has been shown to retard progression of renal disease in diabetic and nondiabetic animals.⁴³ Finally, zinc is an important component of cytoplasmic (Cu-Zn SOD) and extracellular superoxide dismutase, which serves as the frontline of defense against reactive oxygen species. Moreover, zinc deficiency has been shown to aggravate hypertension in SHR.⁴⁴ Given the natural origin of these nutrients, their low toxicity and ready availability, we elected to use this combination instead of more potent but less readily available and potentially toxic compounds, such as, lazaroid or tempol used in previous studies.^14,22

Perspectives
The central findings of this investigation are, first, that SHR consuming a regular diet have renal infiltration of lymphocytes, macrophages, and angiotensin II–positive cells in association with severe hypertension, and second, that an antioxidant-fortified diet reduces renal immune infiltration and ameliorates hypertension.

The observed effects are in agreement with our previous studies in SHR showing that the reduction in immune cell infiltration of the kidney by administration of an immunosuppressive anti-inflammatory drug results in amelioration of hypertension, which is coupled with a decline in renal malondialdehyde content and the number of superoxide-positive cells in the kidney.³¹ As emphasized in a recent review,⁴ oxidative stress may be a cause⁸ as well as a consequence⁴⁵ of hypertension, and if present in the kidney, it may fuel a vicious cycle that includes renal inflammation and sodium retention.³⁴ Although the available data do not allow definitive conclusion as to the primary or secondary nature of the inflammatory process in the pathogenesis of hypertension, the data provide convincing evidence for its role in the maintenance of hypertension.

Oxidative stress has been shown to raise arterial blood pressure by promoting functional nitric oxide deficiency (through NO inactivation and tetrahydrobiopterin depletion) and by augmenting arachidonic acid oxidation and formation of vasoconstrictive prostaglandin F₂. It is therefore not surprising that amelioration of oxidative stress with antioxidant therapy should improve hypertension. However, the mechanism responsible for the antioxidant therapy–induced amelioration of the inflammatory infiltration of the renal tissue shown here is less clear. It should be noted that reactive oxygen species have been shown to activate nuclear factor-B, which can in turn promote transcription of genes encoding proinflammatory cytokines.⁴⁶ This phenomenon can potentially explain the prevention of the inflammatory infiltration of the kidney in the antioxidant-treated SHR-T group. It is of interest that long-term control of hypertension with AT-1 receptor blocker losartan has been recently shown to prevent structural and functional deterioration of kidney in SHR.⁴⁷ However, by attenuating the angiotensin-mediated upregulation of NAD(P)H oxidase, AT-1 receptor blockade exerts an antioxidant action that contributes to its antihypertensive and renal protective properties.

The correlation between the intensity of cellular infiltration and the severity of hypertension in the present study raises the possibility of a cause-effect relation that needs to be explored further. In addition, the present studies confirm that dietary antioxidant treatment improves hypertension in SHR and suggest that this therapeutic approach may be of clinical use.

	Acknowledgments

 
This study was funded in part by a generous grant provided by Thomas Yuen (Dr Vaziri’s laboratory) and FONACYT grant No. S1–2001001097, Venezuela (Dr Rodríguez-Iturbe’s laboratory).

Received August 27, 2002; first decision September 11, 2002; accepted December 5, 2002.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Berry C, Brosnan MJ, Fennell J, Hamilton CA, Dominiczak AF. Oxidative stress and vascular damage in hypertension. Curr Opin Nephrol Hypertens. 2001; 2001: 10: 247–255.[Medline] [Order article via Infotrieve]
2. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens. 2000; 18: 655–673.[CrossRef][Medline] [Order article via Infotrieve]
3. Schnackenberg CG. Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol (Regulatory Physiol). 2002; 282: R335–R342.
4. Wilcox CS. Reactive oxygen species: roles in blood pressure and kidney function. Curr Hypertens Rep. 2002; 4: 160–166.[Medline] [Order article via Infotrieve]
5. Barton CH, Ni Z, Vaziri ND. Enhanced nitric oxide inactivation in aortic coarctation-induced hypertension. Kidney Int. 2001; 60: 1083–1087.[CrossRef][Medline] [Order article via Infotrieve]
6. Makino A, Skelton MM, Zou AP, Roman RJ, Cowley AW Jr. Increased renal medullary oxidative stress produces hypertension. Hypertension. 2002; 39: 667–672.[Abstract/Free Full Text]
7. Zhou XJ, Vaziri ND, Wang XQ, Silva FG, Laszik Z. Nitric oxide synthase expression in hypertension induced by inhibition of glutathione synthase. J Pharmacol Exp Ther. 2002; 300: 762–767.[Abstract/Free Full Text]
8. Vaziri ND, Wang XQ, Oveisi F, Rad B. Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats. Hypertension. 2000; 36: 142–146.[Abstract/Free Full Text]
9. Vaziri ND, Liang K, Ding Y. Increased nitric oxide inactivation by reactive oxygen species in lead-induced hypertension. Kidney Int. 1999; 56: 1492–1498.[CrossRef][Medline] [Order article via Infotrieve]
10. Vaziri ND, Ni Z, Oviesi F, Liang K, Pandian R. Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension. 2002; 39: 135–141.[Abstract/Free Full Text]
11. Roberts CK, Vaziri ND, Wang XQ, Barnard RJ. Enhanced NO inactivation induced by a high fat, refined-carbohydrate diet. Hypertension. 2000; 36: 423–429.[Abstract/Free Full Text]
12. El Midaoui A, de Champlain J. Prevention of hypertension, insulin resistance, and oxidative stress by alpha-lipoic acid. Hypertension. 2002; 39: 303.307.
13. Park JB, Touyz RM, Chen X, Schiffrin EL. Chronic treatment with a superoxide dismutase mimetic prevents remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats. Am J Hypertens. 2002; 15: 78–84.[CrossRef][Medline] [Order article via Infotrieve]
14. Schnackenberg CG, Welch WJ, Wilcox CS. Normalization of blood pressure and renal vascular resistance in SHR with a membrane permeable superoxide dismutase mimetic: Role of nitric oxide. Hypertension. 1998; 32: 59–64.[Abstract/Free Full Text]
15. Schnackenberg CG, Wilcox CS. Two-week administration of tempol attenuates both hypertension and renal excretion of 8-iso prostaglandin f2 alpha. Hypertension. 1999; 33: 424–428.[Abstract/Free Full Text]
16. Wu R, Lamontagne D, de Champlain J. Antioxidative properties of acetylsalicylic acid on vascular tissues from normotensive and spontaneously hypertensive rats. Circulation. 2002; 105: 387–392.[Abstract/Free Full Text]
17. Noguchi T, Ikeda K, Sasaki Y, Yamamoto J, Seki J, Yamagata K, Nara I, Hara H, Kakuta H, Yamori Y. Effects of vitamin E and sesamin on hypertension and cerebral thrombogenesis in stroke-prone spontaneously hypertensive rats. Hypertens Res. 2001; 24: 735–742.[CrossRef][Medline] [Order article via Infotrieve]
18. Chen X, Touyz RM, Park JB, Schiffrin EL. Antioxidant effects of vitamin C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension. 2001; 38: 606–611.[Abstract/Free Full Text]
19. Wilcox CS, Welch WJ. Oxidative stress: cause or consequence of hypertension. Exp Biol Med. 2001; 226: 619–620.[Free Full Text]
20. Cabassi A, Bouchard JF, Dumont EC, Girouard H, Le Jossec M, Lamontagne D, Besner JG, de Champlain J. Effect of antioxidant treatments on nitrate tolerance development in normotensive and hypertensive rats. J Hypertens. 2000; 18: 187–196.[CrossRef][Medline] [Order article via Infotrieve]
21. Vaziri ND, Ding Y, Ni Z. Compensatory up-regulation of nitric oxide synthase isoforms in lead-induced hypertension: reversal by a superoxide dismutase mimetic drug. J Pharmacol Exp Ther. 2001; 298: 679–685.[Abstract/Free Full Text]
22. Vaziri ND, Ni Z, Oveisi F, Trnavsky-Hobbs DL. Effect of antioxidant therapy on blood pressure and NO synthase expression in hypertensive rats. Hypertension. 2000; 36: 957–964.[Abstract/Free Full Text]
23. Wassman S, Laufs U, Stamenkovic D, Linz W, Stasch JP, Ahlbory K, Rosen R, Bohm M, Nickenig G. Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation. 2002; 105: 2083–2091.[Abstract/Free Full Text]
24. Carr A, Frei B. The role of natural antioxidants in preserving the biological activity of endothelium-derived nitric oxide. Free Radic Biol Med. 2000; 28: 1806–1814.[CrossRef][Medline] [Order article via Infotrieve]
25. Zalba G, Beaumont J, San Jose G, Fortuno A, Fortuno MA, Diez J. Vascular oxidant stress: molecular mechanisms and pathophysiological implications. J Physiol Biochem. 2000; 56: 57–64.[Medline] [Order article via Infotrieve]
26. Rathaus A, Bernheim J. Oxygen species in the microvascular environment: regulation of vascular tone and the development of hypertension. Nephrol Dial Transplant. 2002; 17: 216–221.[Medline] [Order article via Infotrieve]
27. Rodríguez-Iturbe B, Pons H, Herrera-Acosta J, Johnson RJ. The role of immunocompetent cells in nonimmune renal disease. Kidney Int. 2001; 59: 1626–1640.[CrossRef][Medline] [Order article via Infotrieve]
28. Rodríguez-Iturbe B, Quiroz Y, Herrera-Acosta J, Johnson RJ, Pons HA. The role of immune cells infiltrating the kidney in the pathogenesis of salt-sensitive hypertension. J Hypertens. 2002; 20 (suppl 3): S9–S14.[Medline] [Order article via Infotrieve]
29. Rodríguez-Iturbe B, Pons H, Quiroz Y, Gordon K, Rincón J, Chávez M, Parra G, Hererra-Acosta J, Gómez-Garre D, Largo R, Egido J, Johnson RJ. Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure. Kidney Int. 2001; 59: 2222–2232.[Medline] [Order article via Infotrieve]
30. Quiroz Y, Pons H, Gordon KL, Rincón J, Chávez M, Parra G, Herrera-Acosta J, Gómez-Garre D, Largo R, Egido J, Johnson RJ, Rodríguez-Iturbe B. Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition. Am J Physiol (Renal Physiol). 2001; 281: F38–F47.
31. Rodríguez-Iturbe B, Quiroz Y, Nava M, Bonet L, Chávez M, Herrea-Acosta J, Johnson RJ, Pons H. Reduction of renal immune infiltration results in blood pressure control in genetically hypertensive rats. Am J Physiol (Renal Physiol). 2002; 282: F191–F201.
32. Alvarez V, Quiroz Y, Nava M, Pons H, Rodríguez-Iturbe B. Renal infiltration of immune cells cause salt-sensitive hypertension following overload proteinuria. Am J Physiol Renal Physiol. 2002; 283: F1132–F1141.[Abstract/Free Full Text]
33. Franco M, Tapia E, Santamaría J, Zafra I, García-Torres R, Gordon K, Pons H, Rodríguez-Iturbe B, Johnson RJ, Herrera-Acosta J. Renal cortical vasoconstriction contributes to the development of salt-sensitive hypertension after angiotensin II exposure. J Am Soc Nephrol. 2001; 12: 2263–2271.[Abstract/Free Full Text]
34. Johnson RJ, Herrera-Acosta J, Schreiner G, Rodríguez-Iturbe B. Subtle acquired renal injury as mechanism of salt-sensitive hypertension. N Engl J Med. 2002 346; 913–923.[Medline] [Order article via Infotrieve]
35. Gonick HC, Ding Y, Bondy SC, Ni Z, Vaziri ND. Lead-induced hypertension: interplay of nitric oxide and reactive oxygen species. Hypertension. 1997; 30: 1487–1492.[Abstract/Free Full Text]
36. Raij L, Azar S, Keane W. Mesangial immune injury, hypertension and progressive damage in Dahl rats. Kidney Int. 1984; 26: 137–143.[Medline] [Order article via Infotrieve]
37. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978; 52: 302–310.[Medline] [Order article via Infotrieve]
38. Roberts CK, Vaziri ND, Liang K, Barnard JR. Reversibility of experimental syndrome X by dietary modification. Hypertension. 2001; 37: 1323–1328.[Abstract/Free Full Text]
39. Swei A, Lacy F, De Lano FA, Schmidt-Schonbein GW. Oxidative stress in the Dahl salt-sensitive rat. Hypertension. 1997; 30: 1628–1633.[Abstract/Free Full Text]
40. Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, Harrison DG. Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation. 1997; 95: 588–593.[Abstract/Free Full Text]
41. Roggensack AM, Zhang Y, Davidge ST. Evidence for peroxynitrite formation in the vasculature of women with preeclampsia. Hypertension. 1999; 33: 83–89.[Abstract/Free Full Text]
42. Higashi Y, Sasaki S, Nakagawa K, Matsura H, Oshima T, Chayama K. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med. 2002; 346: 1954–1952.[Abstract/Free Full Text]
43. Reddi AS, Bollineni JS. Selenium-deficient diet induces renal oxidative stress and injury via TGF-B in normal and diabetic rats. Kidney Int. 2001; 59: 1342–1353.[CrossRef][Medline] [Order article via Infotrieve]
44. Sato M, Yanagisawa H, Nojima Y, Tamura J, Wada O. Zinc deficiency aggravates hypertension in spontaneously hypertensive rats: possible role of Cu/Zn-superoxide dismutase. Clin Exp Hypertens. 2002; 24: 355–370.[CrossRef][Medline] [Order article via Infotrieve]
45. Barton CH, Ni Z, Vaziri ND. Enhanced nitric oxide inactivation in aortic coarctation-induced hypertension. Kidney Int. 2001; 60: 183–187.
46. Lum H, Roebuck KA. Oxidant stress and endothelial cell dysfunction. Am J Physiol (Cell Physiol). 2001; 280: C719–C741.
47. Zhou XJ, Wang XQ, Vaziri ND. Association of renal injury with nitric oxide deficiency in aged spontaneously hypertensive rats: prevention by AT-1 receptor blockade. Kidney Int. 2002; 62: 914–921.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				M. P. Koeners, B. Braam, D. M. van der Giezen, R. Goldschmeding, and J. A. Joles A perinatal nitric oxide donor increases renal vascular resistance and ameliorates hypertension and glomerular injury in adult fawn-hooded hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2008; 294(6): R1847 - R1855. [Abstract] [Full Text] [PDF]

				E. Grossman Does Increased Oxidative Stress Cause Hypertension? Diabetes Care, February 1, 2008; 31(Supplement_2): S185 - S189. [Abstract] [Full Text] [PDF]

				N. Tian, R. S. Moore, S. Braddy, R. A. Rose, J.-W. Gu, M. D. Hughson, and R. D. Manning Jr. Interactions between oxidative stress and inflammation in salt-sensitive hypertension Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3388 - H3395. [Abstract] [Full Text] [PDF]

				J. C. Sullivan, L. Semprun-Prieto, E. I. Boesen, D. M. Pollock, and J. S. Pollock Sex and sex hormones influence the development of albuminuria and renal macrophage infiltration in spontaneously hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1573 - R1579. [Abstract] [Full Text] [PDF]

				Y. Bravo, Y. Quiroz, A. Ferrebuz, N. D. Vaziri, and B. Rodriguez-Iturbe Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension Am J Physiol Renal Physiol, August 1, 2007; 293(2): F616 - F623. [Abstract] [Full Text] [PDF]

				M. Franco, F. Martinez, Y. Quiroz, O. Galicia, R. Bautista, R. J. Johnson, and B. Rodriguez-Iturbe Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R251 - R256. [Abstract] [Full Text] [PDF]

				Z. Wang, I. Armando, L. D. Asico, C. Escano, X. Wang, Q. Lu, R. A. Felder, C. G. Schnackenberg, D. R. Sibley, G. M. Eisner, et al. The elevated blood pressure of human GRK4{gamma} A142V transgenic mice is not associated with increased ROS production Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2083 - H2092. [Abstract] [Full Text] [PDF]

				M. R. Hayden, N. A. Chowdhury, S. A. Cooper, A. Whaley-Connell, J. Habibi, L. Witte, C. Wiedmeyer, C. M. Manrique, G. Lastra, C. Ferrario, et al. Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat Am J Physiol Renal Physiol, February 1, 2007; 292(2): F861 - F867. [Abstract] [Full Text] [PDF]

				P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]

				B. Rodriguez-Iturbe, L. Sepassi, Y. Quiroz, Z. Ni, and N. D. Vaziri Association of mitochondrial SOD deficiency with salt-sensitive hypertension and accelerated renal senescence J Appl Physiol, January 1, 2007; 102(1): 255 - 260. [Abstract] [Full Text] [PDF]

				J. Herrera, A. Ferrebuz, E. G. MacGregor, and B. Rodriguez-Iturbe Mycophenolate Mofetil Treatment Improves Hypertension in Patients with Psoriasis and Rheumatoid Arthritis J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S218 - S225. [Abstract] [Full Text] [PDF]

				U. P. Kodavanti, M. C. Schladweiler, A. D. Ledbetter, R. V. Ortuno, M. Suffia, P. Evansky, J. H. Richards, R. H. Jaskot, R. Thomas, E. Karoly, et al. The Spontaneously Hypertensive Rat: An Experimental Model of Sulfur Dioxide-Induced Airways Disease Toxicol. Sci., November 1, 2006; 94(1): 193 - 205. [Abstract] [Full Text] [PDF]

				M. Miguel, I. Recio, M. Ramos, M. A. Delgado, and M. A. Aleixandre Antihypertensive Effect of Peptides Obtained from Enterococcus faecalis-Fermented Milk in Rats. J Dairy Sci, September 1, 2006; 89(9): 3352 - 3359. [Abstract] [Full Text] [PDF]

				B. Rodriguez-Iturbe and R. J. Johnson Role of inflammatory cells in the kidney in the induction and maintenance of hypertension Nephrol. Dial. Transplant., February 1, 2006; 21(2): 260 - 263. [Full Text] [PDF]

				B. Rodriguez-Iturbe, A. Ferrebuz, V. Vanegas, Y. Quiroz, S. Mezzano, and N. D. Vaziri Early and Sustained Inhibition of Nuclear Factor-{kappa}B Prevents Hypertension in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 51 - 57. [Abstract] [Full Text] [PDF]

				C. S. Wilcox Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R913 - R935. [Abstract] [Full Text] [PDF]

				S. Racasan, B. Braam, H. A. Koomans, and J. A. Joles Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon Am J Physiol Renal Physiol, April 1, 2005; 288(4): F626 - F636. [Abstract] [Full Text] [PDF]

				M. Sugita, H. Sugita, and M. Kaneki Increased Insulin Receptor Substrate 1 Serine Phosphorylation and Stress-Activated Protein Kinase/c-Jun N-Terminal Kinase Activation Associated With Vascular Insulin Resistance in Spontaneously Hypertensive Rats Hypertension, October 1, 2004; 44(4): 484 - 489. [Abstract] [Full Text] [PDF]

				R. M. Touyz Reactive Oxygen Species, Vascular Oxidative Stress, and Redox Signaling in Hypertension: What Is the Clinical Significance? Hypertension, September 1, 2004; 44(3): 248 - 252. [Abstract] [Full Text] [PDF]

				A. R. Chade, M. D. Bentley, X. Zhu, M. Rodriguez-Porcel, S. Niemeyer, B. Amores-Arriaga, C. Napoli, E. L. Ritman, A. Lerman, and L. O. Lerman Antioxidant Intervention Prevents Renal Neovascularization in Hypercholesterolemic Pigs J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1816 - 1825. [Abstract] [Full Text] [PDF]

				B. Rodriguez-Iturbe, N. D. Vaziri, J. Herrera-Acosta, and R. J. Johnson Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all Am J Physiol Renal Physiol, April 1, 2004; 286(4): F606 - F616. [Abstract] [Full Text] [PDF]