Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of renal medullary gene expression

2003 ◽  
Vol 12 (3) ◽  
pp. 229-237 ◽  
Author(s):  
Mingyu Liang ◽  
Baozhi Yuan ◽  
Elizabeth Rute ◽  
Andrew S. Greene ◽  
Michael Olivier ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Time Course ◽  
Expression Patterns ◽  
Renal Medulla ◽  
Temporal Patterns ◽  
Reference Distribution ◽  
Arterial Blood ◽  
Renal Tubular ◽  
Salt Sensitive Hypertension

Dahl salt-sensitive SS and consomic, salt-resistant SS-13BN/Mcw rats possess a highly similar genetic background but exhibit substantial differences in blood pressure salt sensitivity. We used cDNA microarrays to examine sequential changes of mRNA expression of ∼2,000 currently known rat genes in the renal medulla (a tissue critical for long-term blood pressure regulation) in SS and SS-13BN/Mcw rats in response to a high-salt diet (16 h, 3 days, or 2 wk). Differentially expressed genes in each between-group comparison were identified based on a threshold determined experimentally using a reference distribution that was constructed by comparing rats within the same group. A difference analysis of 54 microarrays identified 50 genes that exhibited the most distinct temporal patterns of expression between SS and SS-13BN/Mcw rats over the entire time course. Thirty of these genes could be linked to the regulation of arterial blood pressure or renal injury based on their known involvement in functional pathways such as renal tubular transport, metabolism of vasoactive substances, extracellular matrix formation, and apoptosis. Importantly, the majority of the 30 genes exhibited temporal expression patterns that would be expected to lower arterial pressure and reduce renal injury in SS-13BN/Mcw compared with SS rats. The phenotypic impact of the other 20 genes was less clear. These 50 genes are widely distributed on chromosome 13 and several other chromosomes. This suggested that primary genetic defects, although important, are unlikely to be solely responsible for the full manifestation of this type of hypertension and associated injury phenotypes. In summary, the results of this study identified a number of pathways potentially important for the amelioration of hypertension and renal injury in SS-13BN/Mcw rats, and these results generated a series of testable hypotheses related to the role of the renal medulla in the complex mechanism of salt-sensitive hypertension.

scholarly journals Renal medullary 11β-hydroxysteroid dehydrogenase type 1 in Dahl salt-sensitive hypertension

2008 ◽  
Vol 36 (1) ◽  
pp. 52-58 ◽  
Author(s):  
Yong Liu ◽  
Ravinder J. Singh ◽  
Kristie Usa ◽  
Brian C. Netzel ◽  
Mingyu Liang
Keyword(s):  
Blood Pressure ◽  
Urinary Excretion ◽  
Molecular Mechanisms ◽  
Renal Medulla ◽  
Hydroxysteroid Dehydrogenase ◽  
Induced Hypertension ◽  
Intensive Investigation ◽  
Salt Sensitive Hypertension ◽  
Interfering Rna

The Dahl salt-sensitive rat is a widely used model of human salt-sensitive forms of hypertension. The kidney plays an important role in the pathogenesis of Dahl salt-sensitive hypertension, but the molecular mechanisms involved remain a subject of intensive investigation. Gene expression profiling studies suggested that 11β-hydroxysteroid dehydrogenase type 1 might be dysregulated in the renal medulla of Dahl salt-sensitive rats. Additional analysis confirmed that renal medullary expression of 11β-hydroxysteroid dehydrogenase type 1 was downregulated by a high-salt diet in SS-13BN rats, a consomic rat strain with reduced blood pressure salt sensitivity, but not in Dahl salt-sensitive rats. 11β-Hydroxysteroid dehydrogenase type 1 is known to convert inactive 11-dehydrocorticosterone to active corticosterone. The urinary corticosterone/11-dehydrocorticosterone ratio as well as urinary excretion of corticosterone was higher in Dahl salt-sensitive rats than in SS-13BN rats. Knockdown of renal medullary 11β-hydroxysteroid dehydrogenase type 1 with small-interfering RNA attenuated the early phase of salt-induced hypertension in Dahl salt-sensitive rats and reduced urinary excretion of corticosterone. Knockdown of 11β-hydroxysteroid dehydrogenase type 1 did not affect blood pressure in SS-13BN rats. Long-term attenuation of salt-induced hypertension was achieved with small hairpin RNA targeting renal medullary 11β-hydroxysteroid dehydrogenase type 1. In summary, we have demonstrated that suppression of 11β-hydroxysteroid dehydrogenase type 1 expression in the renal medulla attenuates salt-induced hypertension in Dahl salt-sensitive rats.

The Generation of Kinins in the Blood of Dogs during Hypotension Due to Haemorrhage

1970 ◽  
Vol 39 (3) ◽  
pp. 349-365 ◽  
Author(s):  
H. E. Berry ◽  
J. G. Collier ◽  
J. R. Vane
Keyword(s):  
Blood Pressure ◽  
Time Course ◽  
Venous Pressure ◽  
Venous Blood ◽  
Systemic Circulation ◽  
Substantial Effect ◽  
Mixed Venous Blood ◽  
Shed Blood ◽  
Arterial Blood ◽  
Organ Technique

1. Circulating kinins were detected and continuously assayed during hypotension due to haemorrhage in dogs, using the blood-bathed organ technique and isolated strips of cat jejunum as the assay tissue. 2. In arterial blood kinin concentrations of 1–5 ng/ml were attained after a hypotension of 35–65 mmHg had been maintained for 10–190 min. When portal venous blood was simultaneously assayed kinins appeared earlier and in concentrations 1–2 ng/ml higher than in arterial blood. No differences in time course of kinin generation or in concentration were found when mixed venous blood and arterial blood were compared. In those instances in which the blood pressure was restored to normal by returning the shed blood, kinin formation stopped. 3. Kinin generation was due to the presence in the circulation of a kinin-forming enzyme, such as kallikrein. When kallikrein was infused into the portal vein, it was partially inactivated by the liver. 4. Prolonged intravenous infusions of kallikrein (20–60 mu kg−1 min−1) generated kinins in the circulation in concentrations (1–5 ng/ml) which were well maintained throughout the infusion, demonstrating that kinin generation is not limited by depletion of the precursor kininogen; nevertheless, the effects of kallikrein infusions on the blood pressure and central venous pressure waned. 5. It is concluded that in hypotension due to haemorrhage, an active kallikrein appears in the portal circulation. Delay in the appearance of kallikrein in the systemic circulation may be due to the kallikrein inactivating mechanism of the liver. This inactivating mechanism may fail during shock. Kinins are generated in amounts sufficient to have a substantial effect on the circulation and an influence on the course of events in shock.

Abstract MP57: Chronic Inhibition Of Brain Rhomboid-like Protein 2 (irhom2) Activity Decreases Arterial Blood Pressure In Salt-sensitive Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Mazher Mohammed ◽  
Mona Elgazzaz ◽  
Clara Berdasco ◽  
Eric D Lazartigues
Keyword(s):  
Blood Pressure ◽  
Neutralizing Antibody ◽  
Experimental Models ◽  
Arterial Blood ◽  
Artificial Cerebrospinal Fluid ◽  
Tnf Α ◽  
Significant Attenuation ◽  
Factor Α ◽  
Salt Sensitive Hypertension ◽  
The Brain

We previously reported that ADAM17 (aka tumor necrosis factor-α convertase) is critical for the development of hypertension in experimental models and patients. Recent studies highlighted that ADAM17’s formation of TNF-α relies on prior maturation of this sheddase, controlled by the rhomboid-like protein 2 (iRhom2) specifically in microglia. Genetic deletion of iRhom2 in mice shows significant attenuation of TNF-α and ADAM17 activity in a tissue specific manner. Here, we hypothesized that silencing iRhom2 activity specifically in the brain would decrease blood pressure (BP) in the DOCA-salt model of hypertension, in mice. Uninephrectomized mice were implanted subcutaneously (sc) with DOCA-pellets (50 mg) and provided with 1% saline in drinking water. In addition, mice were chronically implanted with an icv cannula connected to a sc osmotic minipump for delivery of: (1) iRhom2-siRNA (9.6 μg/kg/day), (2) scrambled siRNA (SCR 0.2 μg/kg/day), (3) ADAM17 antibody (ADAM17-Ab; 23.8 μg/kg/day) or (4) artificial cerebrospinal fluid (aCSF) for 2 weeks while BP was recorded by telemetry. DOCA-salt treatment led to a significant increase in BP in the control groups (SCR: 156 ±3 mmHg and aCSF: 161 ±1 mmHg; n=3/group; p<0.001) compared to baseline values (122 ±2 mmHg; n=12). ICV infusion of iRhom2-siRNA or ADAM17 neutralizing antibody for 2-weeks in DOCA-salt-treated mice resulted in a significant attenuation of BP (iRhom2-siRNA: 152 ±2 mmHg and ADAM17-Ab: 151 ±2 mmHg n=3/group, p<0.001). These data suggest that: 1) Selective silencing of iRhom2 from microglia is as potent as ADAM17 neutralization throughout the brain in lowering BP and 2) iRhom2 is a potential new therapeutic target for the treatment of salt-sensitive hypertension.

CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR

2001 ◽  
Vol 280 (1) ◽  
pp. R255-R261 ◽  
Author(s):  
Mong-Heng Wang ◽  
Fan Zhang ◽  
Jackleen Marji ◽  
Barbara A. Zand ◽  
Alberto Nasjletti ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arachidonic Acid ◽  
Antisense Oligonucleotide ◽  
Vascular Reactivity ◽  
Spontaneously Hypertensive Rat ◽  
Mesenteric Arteries ◽  
Arachidonic Acid Metabolite ◽  
Spontaneously Hypertensive ◽  
Arterial Blood ◽  
Renal Tubular

The cytochrome P-450 4A (CYP4A)-derived arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) affects renal tubular and vascular functions and has been implicated in the control of arterial pressure. We examined the effect of antisense oligonucleotide (ODN) to CYP4A1, the low K m arachidonic acid ω-hydroxylating isoform, on vascular 20-HETE synthesis, vascular reactivity, and blood pressure in the spontaneously hypertensive rat (SHR). Administration of CYP4A1 antisense ODN decreased mean arterial blood pressure from 137 ± 3 to 121 ± 4 mmHg ( P < 0.05) after 5 days of treatment, whereas treatment with scrambled antisense ODN had no effect. Treatment with CYP4A1 antisense ODN reduced the level of CYP4A-immunoreactive proteins along with 20-HETE synthesis in mesenteric arterial vessels. Mesenteric arteries from rats treated with antisense ODN exhibited decreased sensitivity to the constrictor action of phenylephrine (EC50 0.69 ± 0.17 vs. 1.77 ± 0.40 μM). Likewise, mesenteric arterioles from antisense ODN-treated rats revealed attenuation of myogenic constrictor responses to increases of transmural pressure. The decreased vascular reactivity and myogenic responses were reversible with the addition of 20-HETE. These data suggest that CYP4A1-derived 20-HETE facilitates myogenic constrictor responses in the mesenteric microcirculation and contributes to pressor mechanisms in SHR.

Sodium-, potassium-, chloride-, and bicarbonate-related effects on blood pressure and electrolyte homeostasis in deoxycorticosterone acetate-treated rats

2008 ◽  
Vol 295 (6) ◽  
pp. F1752-F1763 ◽  
Author(s):  
Agata Ziomber ◽  
Agnes Machnik ◽  
Anke Dahlmann ◽  
Peter Dietsch ◽  
Franz-Xaver Beck ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Male Rats ◽  
Sodium Potassium ◽  
Arterial Blood ◽  
Electrolyte Homeostasis ◽  
Water Mass Balance ◽  
Group 2 ◽  
Total Body ◽  
Salt Sensitive Hypertension ◽  
Volume Retention

Na+ loading without Cl− fails to increase blood pressure in the DOCA model. We compared the changes in the total body (TB) effective Na+, K+, Cl−, and water (TBW) content as well as in intracellular (ICV) or extracellular (ECV) volume in rats receiving DOCA-NaCl, DOCA-NaHCO3, or DOCA-KHCO3. We divided 42 male rats into 5 groups. Group 1 was untreated, group 2 received 1% NaCl, and groups 3, 4, and 5 were treated with DOCA and received 1% NaCl, 1.44% NaHCO3, or 1.7% KHCO3 to drink. We measured mean arterial blood pressure (MAP) directly after 3 wk. Tissue electrolyte and water content was measured by chemical analysis. Compared with control rats, DOCA-NaCl increased MAP while DOCA-NaHCO3 and DOCA-KHCO3 did not. DOCA-NaCl increased TBNa+ 26% but only moderately increased TBW. DOCA-NaHCO3 led to similar TBNa+ excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHCO3 did not affect TBNa+ or volume. At a given TB(Na++K+) and TBW, MAP in DOCA-NaCl rats was higher than in control, DOCA-NaHCO3, and DOCA-KHCO3 rats, indicating that hypertension in DOCA-NaCl rats was not dependent on TB(Na++K+) and water mass balance. Skin volume retention was hypertonic compared with serum and paralleled hypertension in DOCA-NaCl rats. These rats had higher TB(Na++K+)-to-TBW ratio in accumulated fluid than DOCA-NaHCO3 rats. DOCA-NaCl rats also had increased intracellular Cl− concentrations in skeletal muscle. We conclude that excessive cellular electrolyte redistribution and/or intracellular Na+ or Cl− accumulation may play an important role in the pathogenesis of salt-sensitive hypertension.

scholarly journals Interactions between 11β-hydroxysteroid dehydrogenase and COX-2 in kidney

2005 ◽  
Vol 288 (6) ◽  
pp. R1767-R1773 ◽  
Author(s):  
Bing Yao ◽  
Raymond C. Harris ◽  
Ming-Zhi Zhang
Keyword(s):  
Blood Pressure ◽  
Renal Medulla ◽  
Hydroxysteroid Dehydrogenase ◽  
High Salt ◽  
Adult Rats ◽  
Water Excretion ◽  
Suckling Rats ◽  
Apparent Mineralocorticoid Excess ◽  
Cox 2 ◽  
Salt Sensitive Hypertension

The syndrome of apparent mineralocorticoid excess (SAME) is an autosomal recessive form of salt-sensitive hypertension caused by deficiency of the kidney type 2 11β-hydroxysteroid dehydrogenase (11βHSD2). In this disorder, cortisol is not inactivated by 11βHSD2, occupies mineralocorticoid receptors (MRs), and causes excessive sodium retention and hypertension. In renal medulla, prostaglandins derived from cyclooxygenase-2 (COX-2) stimulate sodium and water excretion, and renal medullary COX-2 expression increases after mineralocorticoid administration. We investigated whether medullary COX-2 also increases in rats with 11βHSD2 inhibition and examined its possible role in the development of hypertension. 11βHSD2 inhibition increased medullary and decreased cortical COX-2 expression in adult rats and induced high blood pressure in high-salt-treated rats. COX-2 inhibition had no effect on blood pressure in control animals but further increased blood pressure in high-salt-treated rats with 11βHSD2 inhibition. COX-1 inhibition had no effect on blood pressure in either control or experimental animals. 11βHSD2 inhibition also led to medullary COX-2 increase and cortical COX-2 decrease in weaning rats, primarily through activation of MRs. In the suckling rats, medullary COX-2 expression was very low, consistent with a urinary concentrating defect. 11βHSD2 inhibition had no effect on either cortical or medullary COX-2 expression in the suckling rats, consistent with low levels of circulating corticosterone in these animals. These data indicate that COX-2 plays a modulating role in the development of hypertension due to 11βHSD2 deficiency and that 11βHSD2 regulates renal COX-2 expression by preventing glucocorticoid access to MRs during postnatal development.

scholarly journals Renal inflammation and elevated blood pressure in a mouse model of reduced β-ENaC

2011 ◽  
Vol 301 (2) ◽  
pp. F443-F449 ◽  
Author(s):  
Heather A. Drummond ◽  
Samira C. Grifoni ◽  
Ahmed Abu-Zaid ◽  
Monette Gousset ◽  
Rumbidayzi Chiposi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renal Injury ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Renal Inflammation ◽  
Arterial Blood ◽  
Collagen Iii ◽  
Renal Changes ◽  
Kidney Blood Flow

Previous studies suggest β-epithelial Na+ channel protein (β-ENaC) may mediate myogenic constriction, a mechanism of blood flow autoregulation. A recent study demonstrated that mice with reduced levels of β-ENaC (β-ENaC m/m) have delayed correction of whole kidney blood flow responses, suggesting defective myogenic autoregulatory capacity. Reduced renal autoregulatory capacity is linked to renal inflammation, injury, and hypertension. However, it is unknown whether β-ENaC m/m mice have any complications associated with reductions in autoregulatory capacity such as renal inflammation, injury, or hypertension. To determine whether the previously observed altered autoregulatory control was associated with indicators of renal injury, we evaluated β-ENaC m/m mice for signs of renal inflammation and tissue remodeling using marker expression. We found that inflammatory and remodeling markers, such as IL-1β, IL-6, TNF-α, collagen III and transforming growth factor-β, were significantly upregulated in β-ENaC m/m mice. To determine whether renal changes were associated with changes in long-term control of blood pressure, we used radiotelemetry and found that 5-day mean arterial blood pressure (MAP) was significantly elevated in β-ENaC m/m (120 ± 3 vs. 105 ± 2 mmHg, P = 0.016). Our findings suggest loss of β-ENaC is associated with early signs of renal injury and increased MAP.

HO-1 induction lowers blood pressure and superoxide production in the renal medulla of angiotensin II hypertensive mice

2007 ◽  
Vol 292 (4) ◽  
pp. R1472-R1478 ◽  
Author(s):  
Trinity Vera ◽  
Silvia Kelsen ◽  
Licy L. Yanes ◽  
Jane F. Reckelhoff ◽  
David E. Stec
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Renal Medulla ◽  
Superoxide Production ◽  
Ros Generation ◽  
Heme Oxygenase 1 ◽  
Ang Ii ◽  
Arterial Blood ◽  
Cobalt Protoporphyrin ◽  
Catalase Protein

Heme oxygenase-1 (HO-1) induction can attenuate the development of angiotensin II (ANG II)-dependent hypertension. However, the mechanism by which HO-1 lowers blood pressure in this model is not clear. The goal of this study was to test the hypothesis that induction of HO-1 in the kidney can attenuate the increase in reactive oxygen species (ROS) generation in the kidney that occurs during ANG II-dependent hypertension. Mice were divided into four groups, control (Con), cobalt protoporphyrin (CoPP), ANG II, and ANG II + CoPP. CoPP treatment (50 mg/kg) was administered in a single subcutaneous injection 2 days prior to implantation of an osmotic minipump that infused ANG II at a rate of 1 μg·kg−1·min−1. At the end of this period, mean arterial blood pressure (MAP) averaged 93 ± 5, 90 ± 5, 146 ± 8, and 105 ± 6 mmHg in Con, CoPP-, ANG II-, and ANG II + CoPP-treated mice. To determine whether HO-1 induction resulted in a decrease in ANG II-stimulated ROS generation in the renal medulla, superoxide production was measured. Medullary superoxide production was increased by ANG II infusion and normalized in mice pretreated with CoPP. The reduction in ANG II-mediated superoxide production in the medulla with CoPP was associated with a decrease in extracellular superoxide dismutase protein but an increase in catalase protein and activity. These results suggest that reduction in superoxide and possibly hydrogen peroxide production in the renal medulla may be a potential mechanism by which induction of HO-1 with CoPP lowers blood pressure in ANG-II dependent hypertension.

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