Hypoxia-Inducible Factor Prolyl-Hydroxylase 2 Senses High-Salt Intake to Increase Hypoxia Inducible Factor 1α Levels in the Renal Medulla

HIF prolyl-hydroxylase 2 (PHD2) is an enzyme to promote the degradation of transcription factor hypoxia inducible factor (HIF)-1α. We have previously shown that high salt intake stimulates the expression of microRNA (miR)-429, which promotes the decay of HIF prolyl-hydroxylase 2 (PHD2) mRNA, and that reduction of PHD2 mRNA level leads to the accumulation of HIF-1α and activation of many HIF-1α-regulated antihypertensive genes such as nitric oxide synthase (NOS) 2 and heme oxygenase 1 in the renal medulla. This miR-429-mediated regulation of PHD2/HIF-1α pathway is an important molecular adaptation to promote extra sodium excretion and maintain blood pressure. However the high salt-induced increase in the renal medullary miR-429 level was impaired in Dahl S rat, a salt-sensitive hypertension model. The present study determined whether overexpression of miR-429 would reduce the levels of PHD2 mRNA, increase the expression of HIF-1α target genes in the renal medulla, and consequently attenuate salt-sensitive hypertension in Dahl S rats. Renal medullary miR-429 levels were increased by 2-fold via transfection of miR-429-expressing plasmid into the renal medulla in Dahl S rats, which was accompanied by 40% (0.4 of 1) decrease in PHD2 mRNA levels and 2-fold increase in NOS2 mRNA expression compared with scramble-miR-treated rats. Functionally, chronic high salt-induced sodium retention was remarkably reduced from 28.6 ± 2.4 mmole/kg in control rats to 18.5 ± 1.6 mmole/kg in miR-429-treated rats. Furthermore, hypertension induced by 2-week high salt intake was significantly attenuated in miR-429-treated rats. The mean arterial pressure in these Dahl S rats was 111.8 ± 1.7 mmHg on a low salt diet, 143.7 ± 4.1 on a high salt diet, and 128.6 ± 2.2 on a high salt diet treated with miR-429 plasmids, respectively. These results suggest that the impaired miR-429-mediated PHD2 inhibition in response to high salt intake in the renal medulla may represent a novel mechanism for hypertension in Dahl S rats and that correction of this impairment in miR-429 could be a therapeutic approach for salt-sensitive hypertension.

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ROS Production Is Increased in the Kidney but Not in the Brain of Dahl Rats With Salt Hypertension Elicited in Adulthood

Physiological Research ◽

10.33549/physiolres.933054 ◽

2015 ◽

pp. 303-312 ◽

Cited By ~ 5

Author(s):

M. VOKURKOVÁ ◽

H. RAUCHOVÁ ◽

L. ŘEZÁČOVÁ ◽

I. VANĚČKOVÁ ◽

J. ZICHA

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Nadph Oxidase ◽

Salt Intake ◽

Renal Medulla ◽

High Salt ◽

Ros Production ◽

High Salt Intake ◽

Salt Hypertension ◽

The Brain

Enhanced production of superoxide radicals by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase in the brain and/or kidney of salt hypertensive Dahl rats has been proposed to participate in the pathogenesis of this form of experimental hypertension. Most information was obtained in young Dahl salt-sensitive (DS) rats subjected to high salt intake prior to sexual maturation. Therefore, the aim of our study was to investigate whether salt hypertension induced in adult DS rats is also accompanied with a more pronounced oxidative stress in the brain or kidney as compared to Dahl salt-resistant (DR) controls. NADPH oxidase activity as well as the content of thiobarbituric acid-reactive substances (TBARS) and conjugated dienes (oxidative index), which indicate a degree of lipid peroxidation, were evaluated in two brain regions (containing either hypothalamic paraventricular nucleus or rostral ventrolateral medulla) as well as in renal medulla and cortex. High salt intake induced hypertension in DS rats but did not modify blood pressure in DR rats. DS and DR rats did not differ in NADPH oxidase-dependent production of ROS, TBARS content or oxidative index in either part of the brain. In addition, high-salt diet did not change significantly any of these brain parameters. In contrast, the enhanced NADPH oxidase-mediated ROS production (without significant signs of increased lipid peroxidation) was detected in the renal medulla of salt hypertensive DS rats. Our findings suggest that there are no signs of enhanced oxidative stress in the brain of adult Dahl rats with salt hypertension induced in adulthood.

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High salt intake increases endothelin B receptor function in the renal medulla of rats

Life Sciences ◽

10.1016/j.lfs.2015.12.038 ◽

2016 ◽

Vol 159 ◽

pp. 144-147 ◽

Cited By ~ 3

Author(s):

Chunhua Jin ◽

Joshua S. Speed ◽

David M. Pollock

Keyword(s):

Salt Intake ◽

Renal Medulla ◽

High Salt ◽

Receptor Function ◽

Endothelin B Receptor ◽

High Salt Intake ◽

Endothelin B

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Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure

AJP Renal Physiology ◽

10.1152/ajprenal.00232.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. F542-F549 ◽

Cited By ~ 54

Author(s):

Wenling Ye ◽

Hui Zhang ◽

Elaine Hillas ◽

Donald E. Kohan ◽

R. Lance Miller ◽

...

Keyword(s):

Blood Pressure ◽

Salt Intake ◽

Renal Medulla ◽

Interstitial Cells ◽

High Salt ◽

Salt Loading ◽

Arterial Blood ◽

High Salt Intake ◽

Cox 2 ◽

Cox 1

Expression of cyclooxygenase (COX)-2, but not COX-1, in the renal medulla is stimulated by chronic salt loading; yet the functional implication of this phenomenon is incompletely understood. The present study examined the cellular localization and antihypertensive function of high-salt-induced COX-2 expression in the renal medulla, with a parallel assessment of the function of COX-1. COX-2 protein expression in response to high-salt loading, assessed by immunostaining, was found predominantly in inner medullary interstitial cells, whereas COX-1 protein was abundant in collecting duct (CD) and inner medullary interstitial cells and was not affected by high salt. We compared mRNA expressions of COX-1 and COX-2 in CD vs. non-CD cells isolated from aquaporin 2-green fluorescent protein transgenic mice. A low level of COX-2 mRNA, but a high level of COX-1 mRNA, as determined by real-time RT-PCR, was detected in CD compared with non-CD segments. During high-salt intake, chronic infusions of the COX-2 blocker NS-398 and the COX-1 blocker SC-560 into the renal medulla of Sprague-Dawley rats for 5 days induced ∼30- and 15-mmHg increases in mean arterial pressure, respectively. During similar high-salt intake, COX-1 knockout mice exhibited a gradual, but significant, increase in systolic blood pressure that was associated with a marked suppression of urinary PGE2 excretion. Therefore, we conclude that the two COX isoforms in the renal medulla play a similar role in the stabilization of arterial blood pressure during salt loading.

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High Salt Intake and Stroke: Meta-analysis of the Epidemiologic Evidence

CNS Neuroscience & Therapeutics ◽

10.1111/j.1755-5949.2012.00355.x ◽

2012 ◽

Vol 18 (8) ◽

pp. 691-701 ◽

Cited By ~ 35

Author(s):

Xiu-Yang Li ◽

Xian-Lei Cai ◽

Ping-Da Bian ◽

Liu-Ru Hu

Keyword(s):

Salt Intake ◽

Meta Analysis ◽

High Salt ◽

Epidemiologic Evidence ◽

High Salt Intake

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High Salt Intake Delayed Angiotensin II-Induced Hypertension in Mice With a Genetic Variant of NADPH Oxidase

American Journal of Hypertension ◽

10.1038/ajh.2010.173 ◽

2011 ◽

Vol 24 (1) ◽

pp. 114-118 ◽

Cited By ~ 18

Author(s):

M. Z. Haque ◽

D. S. A. Majid

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Genetic Variant ◽

Salt Intake ◽

High Salt ◽

High Salt Intake ◽

Induced Hypertension

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Differential responses to salt supplementation in adult male and female rat adrenal glands following intrauterine growth restriction

Journal of Endocrinology ◽

10.1530/joe-10-0421 ◽

2011 ◽

Vol 209 (1) ◽

pp. 85-94 ◽

Cited By ~ 3

Author(s):

Karine Bibeau ◽

Mélissa Otis ◽

Jean St-Louis ◽

Nicole Gallo-Payet ◽

Michèle Brochu

Keyword(s):

Protein Expression ◽

Adrenal Glands ◽

Salt Intake ◽

High Salt ◽

Receptor Subtypes ◽

Mrna Levels ◽

Female Rat ◽

Angiotensin Ii Receptor ◽

Intrauterine Growth ◽

High Salt Intake

In low sodium-induced intrauterine growth restricted (IUGR) rat, foetal adrenal steroidogenesis as well as the adult renin–angiotensin–aldosterone system (RAAS) is altered. The aim of the present study was to determine the expression of cytochrome P450 aldosterone synthase (P450aldo) and of angiotensin II receptor subtypes 1 (AT1R) and 2 (AT2R) in adult adrenal glands and whether this expression could be influenced by IUGR and by high-salt intake in a sex-specific manner. After 6 weeks of 0.9% NaCl supplementation, plasma renin activity, P450aldo expression and serum aldosterone levels were decreased in all groups. In males, IUGR induced an increase in AT1R, AT2R, and P450aldo levels, without changes in morphological appearance of the zona glomerulosa (ZG). By contrast, in females, IUGR had no effect on the expression of AT1R, but increased AT2R mRNA while decreasing protein expression of AT2R and P450aldo. In males, salt intake in IUGR rats reduced both AT1R mRNA and protein, while for AT2R, mRNA levels decreased whereas protein expression increased. In females, salt intake reduced ZG size in IUGR but had no affect on AT1R or AT2R expression in either group. These results indicate that, in response to IUGR and subsequently to salt intake, P450aldo, AT1R, and AT2R levels are differentially expressed in males and females. However, despite these adrenal changes, adult IUGR rats display adequate physiological and adrenal responses to high-salt intake, via RAAS inhibition, thus suggesting that extra-adrenal factors likely compensate for ZG alterations induced by IUGR.

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