Effects of estradiol on renal cyclic guanosine monophosphate and oxidative stress in spontaneously hypertensive rats

Sullivan, Jennifer C.; Pardieck, Jennifer; Brinson, Krystal N.; Kang, Kyu Tae

doi:10.1016/j.genm.2009.09.003

Cited by 12 publications

(12 citation statements)

References 57 publications

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“…Consistent with our previous report, male SHR had higher blood pressures than females at baseline and a greater increase in blood pressure in response to ANG II infusion than female SHR at all time points (47). Compared with baseline, ANG II infusion significantly increased blood pressure in males after 5 days of ANG II infusion and after 8 days in females (percent increase in MAP: males, 19 Ϯ 3%; females, 12 Ϯ 2%; P Ͻ 0.05).…”

Section: Resultssupporting

confidence: 90%

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Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

Bhatia¹,

Elmarakby

El-Remessey³

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Bhatia K, Elmarakby AA, El-Remessey A, Sullivan JC. Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 302: R274 -R282, 2012. First published November 2, 2011; doi:10.1152/ajpregu.00546.2011.-NADPH oxidase has been implicated in ANG II-induced oxidative stress and hypertension in males; however, the contribution of oxidative stress to ANG II hypertension in females is unknown. In the present study, we tested the hypothesis that greater antioxidant capacity in female spontaneously hypertensive rats (SHR) blunts ANG II-induced oxidative stress and hypertension relative to males. Whole body and renal cortical oxidative stress levels were assessed in female and male SHR left untreated or following 2 wk of chronic ANG II infusion. Chronic ANG II infusion increased NADPH oxidase enzymatic activity in the renal cortex of both sexes; however, this increase only reached significance in female SHR. In contrast, male SHR demonstrated a greater increase in all measurements of reactive oxygen species production in response to chronic ANG II infusion. ANG II infusion increased plasma superoxide dismutase activity only in female SHR (76 Ϯ 9 vs. 190 Ϯ 7 Units·ml Ϫ1 ·mg Ϫ1 , P Ͻ 0.05); however, cortical antioxidant capacity was unchanged by ANG II in either sex. To assess the functional implication of alterations in NADPH enzymatic activity and oxidative stress levels following ANG II infusion, additional experiments assessed the ability of the in vivo antioxidant apocynin to modulate ANG II hypertension. Apocynin significantly blunted ANG II hypertension in male SHR (174 Ϯ 2 vs. 151 Ϯ 1 mmHg, P Ͻ 0.05), with no effect in females (160 Ϯ 11 vs. 163 Ϯ 10 mmHg). These data suggest that ANG II hypertension in male SHR is more dependent on increases in oxidative stress than in female SHR. superoxide; kidney; apocynin; NADPH oxidase THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) is important in the regulation of body fluid and blood pressure homeostasis, and overactivation of the RAAS contributes to the development of numerous pathophysiological processes (20,21,40). There is an expanding literature regarding sex differences in the expression of RAAS components, as well as in functional responses to RAAS activation to both acute and chronic ANG II infusion (24,25,36,38,46). We recently published that greater levels of the vasodilatory peptide ANG (1-7) contribute to sex differences in the hypertensive response to chronic ANG II infusion in spontaneously hypertensive rats (SHR), although it is unknown whether there are additional molecular mechanism(s) contributing to sex differences in the blood pressure response to ANG II. Activation of angiotensin type 1 (AT 1 ) receptors mediate most well-known biological functions of ANG II, including the stimulation of oxidative stress, and female SHR have fewer AT 1 receptors than male SHR (43). However, little is known regarding the relative contribution of ANG II-mediated oxidative ...

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Section: Resultssupporting

confidence: 90%

“…Renal cortexes were homogenized for determination of NADPH oxidase enzymatic activity and basal O 2 Ϫ levels via lucigenin chemiluminescence, as previously described (47). NADPH oxidase activity was measured in the presence of 100 mol/l NADPH (Sigma, St. Louis, MO) and incubated with lucigenin (Sigma; 5 mol/l).…”

Section: Animalsmentioning

confidence: 99%

Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

Bhatia¹,

Elmarakby

El-Remessey³

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, manipulation of female sex hormones using ovariectomy and estradiol replacement did not alter NOS enzymatic activity in the renal inner medulla. This is consistent with our previous findings that manipulation of female sex hormones did not alter renal cortical NOS activity, expression, or phosphorylation status in female SHR (49). In contrast to our findings, medullary NOS expression has been shown to be altered by ovariectomy in both the young female SD rats and the aged Dahl rats (30,36), suggesting a strainspecific effect of female sex hormones on NOS.…”

Section: Fig 3 Nos Enzymatic Activity and Expression In The Renal Isupporting

confidence: 92%

Renal NOS activity, expression, and localization in male and female spontaneously hypertensive rats

Sullivan

Pardieck

Hyndman

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Sullivan JC, Pardieck JL, Hyndman KA, Pollock JS. Renal NOS activity, expression, and localization in male and female spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 298: R61-R69, 2010. First published November 4, 2009 doi:10.1152/ajpregu.00526.2009.-The goal of this study was to examine the status of the renal nitric oxide (NO) system by determining NO synthase (NOS) isoform activity and expression within the three regions of the kidney in 14-wk-old male and female spontaneously hypertensive rats (SHR). NOS activity, and NOS1 and NOS3 protein expressions and localization were comparable in the renal cortex and outer medulla of male and female SHR. In contrast, male SHR had significantly less NOS1 and NOS3 enzymatic activity (0 Ϯ 5 and 53 Ϯ 7 pmol ⅐ mg Ϫ1 ⅐ 30 min Ϫ1 , respectively) compared with female SHR (37 Ϯ 16 and 172 Ϯ 40 pmol ⅐ mg Ϫ1 ⅐ 30 min Ϫ1 , respectively). Lower levels of inner medullary NOS1 activity in male SHR were associated with less NOS1 protein expression [45 Ϯ 7 relative densitometric units (RDU)] and fewer NOS1-positive cells in the renal inner medulla compared with female SHR (79 Ϯ 12 RDU). Phosphorylation of NOS3 is an important determinant of NOS activity. Male SHR had significantly greater phosphorylation of NOS3 on threonine 495 in the renal cortex compared with females (0.25 Ϯ 0.05 vs. 0.15 Ϯ 0.06 RDU). NOS3 phosphorylation was comparable in males and females in the other regions of the kidney. cGMP levels were measured as an indirect index of NO production. cGMP levels were significantly lower in the renal cortex (0.08 Ϯ 0.01 pmol/mg) and inner medulla (0.43 Ϯ 0.02 pmol/mg) of male SHR compared with females (cortex: 0.14 Ϯ 0.02 pmol/mg; inner medulla: 0.56 Ϯ 0.02 pmol/mg). Our data suggest that the effect of the sex of the animal on NOS activity and expression is different in the three regions of the SHR kidney and supports the hypothesis that male SHR have lower NO bioavailability compared with females. nitric oxide synthase; kidney; sex; gender; cGMP NITRIC OXIDE (NO) is an important regulator of blood pressure and kidney function (3,15,43). Therefore, it is not surprising that NO deficiencies have been linked with hypertension and the progression of chronic renal disease in both patients and experimental animals (2, 3, 45). All three NO synthase (NOS) isoforms have been localized to the kidney (1), and intrarenal inhibition of NOS has been shown to increase blood pressure (32). NOS1 (neuronal NOS) is predominantly localized in the macula densa, neurons, Bowman's capsule, and collecting duct, where it participates in the control of glomerular hemodynamics, renin release, and sodium excretion (1,24,46). Expression of NOS2 (inducible NOS) protein has been difficult to reproducibly detect in the normal kidney; however, there appears to be NOS2 mRNA in the medullary thick ascending limb (34). NOS3 (endothelial NOS) is localized in vascular endothelial cells and tubules, where it is important in the maintenance of glomerular filtration rate, vascular tone, and...

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“…OVX was also not associated with significant changes in NOS3 phosphorylation on serine residue 1177. This result is consistent with previous reports in SHR directly measuring NOS3 phosphorylation and studies in female DS rats, which found that expression of phospho-Akt is not altered by OVX or estrogen supplementation (22,44). The protein kinase Akt increases NOS3 activity by enhancing its phosphorylation on Ser-1177 (9).…”

Section: Intact Ns Intact Hs Ovx Ns Ovx Hssupporting

confidence: 93%

“…Female sex hormones consistently increase NO production in vitro (32), although in vivo studies have yielded conflicting results (11). Consistent with our current results, we have previously published that manipulation of female sex hormones in SHR does not alter NOS enzymatic activity or expression in the renal IM (45) or cortex (44). In agreement with our results, OVX in Sprague-Dawley rats (33), DS rats (on 0.1% NaCl) (22), or Fischer-344 rats (37) does not alter renal NOS expression.…”

Section: Intact Ns Intact Hs Ovx Ns Ovx Hssupporting

confidence: 90%

Female sex hormones protect against salt-sensitive hypertension but not essential hypertension

Brinson

Rafikova

Sullivan

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Brinson KN, Rafikova O, Sullivan JC. Female sex hormones protect against salt-sensitive hypertension but not essential hypertension. Am J Physiol Regul Integr Comp Physiol 307: R149 -R157, 2014. First published May 14, 2014 doi:10.1152/ajpregu.00061.2014.-Initial studies found that female Dahl salt-sensitive (DS) rats exhibit greater blood pressure (BP) salt sensitivity than female spontaneously hypertensive rats (SHR). On the basis of the central role played by NO in sodium excretion and BP control, we further tested the hypothesis that blunted increases in BP in female SHR will be accompanied by greater increases in renal inner medullary nitric oxide synthase (NOS) activity and expression in response to a high-salt (HS) diet compared with DS rats. Gonad-intact and ovariectomized (OVX) female SHR and DS rats were placed on normal salt (NS; 0.4% salt) or HS (4% salt) diet for 2 wk. OVX did not alter BP in SHR, and HS diet produced a modest increase in BP. OVX significantly increased BP in DS rats on NS; HS further increased BP in all DS rats, although OVX had a greater increase in BP. Renal inner medullary NOS activity, total NOS3 protein, and NOS3 phosphorylated on serine residue 1177 were not altered by salt or OVX in either strain. NOS1 protein expression, however, significantly increased with HS only in SHR, and this corresponded to an increase in urinary nitrate/nitrite excretion. SHR also exhibit greater NOS1 and NOS3 protein expression than DS rats. These data indicate that female sex hormones offer protection against HS-mediated elevations in BP in DS rats but not SHR. We propose that the relative resistance to HS-mediated increases in BP in SHR is related to greater NOS expression and the ability to increase NOS1 protein expression compared with DS rats. nitric oxide; Dahl-salt sensitive rats; ovariectomy; spontaneously hypertensive rats SALT SENSITIVITY OF BLOOD pressure (BP) is associated with an increased risk for the development of hypertension and cardiovascular disease. Among women, the prevalence of salt sensitivity increases following both surgical and natural menopause (14, 38), suggesting that the loss of ovarian hormones renders women prone to salt sensitivity and increases their risk of developing hypertension (38). This is further supported by studies in experimental animals; surgical ovariectomy (OVX) increases the BP response to salt in many rat strains, including Dahl salt-sensitive (DS) and Dahl salt-resistant rats (59), mRen(2).Lewis rats (7), Sprague-Dawley rats treated with aldosterone (57), and spontaneously hypertensive rats (SHR) (10). These data suggest that female sex hormones are critical in influencing sodium handling and BP regulation; however, the mechanisms responsible continue to be investigated.Salt-sensitive hypertension has been linked to the reninangiotensin system, as well as a decrease in NO production and bioavailability (8,19,53). There is ample evidence in the literature supporting a role for increased ANG II and AT 1 receptor activation in female experimental an...

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Effects of estradiol on renal cyclic guanosine monophosphate and oxidative stress in spontaneously hypertensive rats

Cited by 12 publications

References 57 publications

Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

Renal NOS activity, expression, and localization in male and female spontaneously hypertensive rats

Female sex hormones protect against salt-sensitive hypertension but not essential hypertension

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