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

Sullivan, Jennifer C.; Pardieck, Jennifer; Hyndman, Kelly A.; Pollock, Jennifer S.

doi:10.1152/ajpregu.00526.2009

Cited by 61 publications

(76 citation statements)

References 55 publications

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“…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%

“…We previously reported that female SHR have greater renal inner medullary NOS activity and NOS1 protein expression than males, and female SHR are more dependent on NOS to maintain their BP than males (2,45). Relative to SHR, DS rats have been suggested to be an NO-deficient rat strain (1,4,59), although few studies have directly compared NOS in the two strains.…”

Section: Intact Ns Intact Hs Ovx Ns Ovx Hsmentioning

confidence: 99%

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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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Section: Intact Ns Intact Hs Ovx Ns Ovx Hssupporting

confidence: 90%

Section: Intact Ns Intact Hs Ovx Ns Ovx Hsmentioning

confidence: 99%

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

Brinson

Rafikova

Sullivan

2014

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

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“…Future studies will directly address this question. ANG II stimulation of NADPH oxidase has been shown to reduce nitric oxide (NO) bioavailability in kidneys of male SHR (2), and we have previously published that female SHR have greater NO bioavailability in the renal cortex than male SHR, independent of alterations in NO synthase activity or expression (48). We proposed that greater NO bioavailability in females was the result of less scavenging of NO by O 2 ·Ϫ (50); therefore, we hypothesize that enhanced NO bioavailability may mitigate ANG II-induced increases in blood pressure (BP) to a greater extent in female SHR.…”

Section: Discussionmentioning

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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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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“…Isolated CDs were immediately processed for Western blotting or incubated with Hank’s Balanced Salt solution + 250 μM L-arginine + 200U/ml superoxide dismutase for 1 h for nitrite measurements. Western blots were performed as previously described 6 , and antibodies are listed in Table S1.…”

Section: Methodsmentioning

confidence: 99%

Renal Collecting Duct NOS1 Maintains Fluid–Electrolyte Homeostasis and Blood Pressure

et al. 2013

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Nitric oxide is a pro-natriuretic and pro-diuretic factor. The highest renal nitric oxide synthase (NOS) activity is found in the inner medullary collecting duct (IMCD). The collecting duct (CD) is the site of daily fine-tune regulation of sodium balance, and led us to hypothesize that a CD specific deletion of NOS1 would result in an impaired ability to excrete a sodium load leading to a salt-sensitive blood pressure phenotype. We bred AQP2-CRE mice with NOS1 floxed mice to produce flox control and CD-specific NOS1 knockout (CDNOS1KO) littermates. Collecting ducts from CDNOS1KO mice produced 75% less nitrite and urinary nitrite+nitrate (NOx) excretion was significantly blunted in the knockout genotype. When challenged with high dietary sodium, CDNOS1KO mice showed significantly reduced urine output, sodium, chloride and NOx excretion, and increased mean arterial pressure relative to flox control mice. In humans, urinary NOx is a newly identified biomarker for the progression of hypertension. These findings reveal that NOS1 in the CD is critical in the regulation of fluid-electrolyte balance, and this new genetic model of CD NOS1 gene deletion will be a valuable tool to study salt-dependent blood pressure mechanisms.

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

Cited by 61 publications

References 55 publications

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

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

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

Renal Collecting Duct NOS1 Maintains Fluid–Electrolyte Homeostasis and Blood Pressure

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