Abstract P035: Prostaglandin Ep4 Receptors In Kidney Epithelial Cells Promote Resistance To Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Ting Yang ◽  
Chengcheng Song ◽  
Matthew A Sparks ◽  
Beverly H Koller ◽  
Thomas M Coffman
Keyword(s):  
Blood Pressure ◽  
Epithelial Cells ◽  
Collecting Duct ◽  
Weight Ratio ◽  
Pressure Control ◽  
Prostaglandin E ◽  
Ang Ii ◽  
Blood Pressure Elevation ◽  
Adult Mice ◽  
Kidney Epithelial Cells

A role for prostanoids in blood pressure control is demonstrated by clinical studies showing that use of nonsteroidal anti-inflammatory drugs, which block all the prostanoid production, is associated with hypertension. Prostaglandin E 2 (PGE 2 ) is a major prostanoid produced by the kidney and its actions are mediated by four E-prostanoid (EP) receptors: EP1-EP4. In previous studies, we found that conditional deletion of EP4R from all tissues in adult mice dramatically exaggerates Ang II-dependent hypertension, suggesting a powerful effect of EP4R to resist blood pressure elevation. We also found that elimination of EP4R from vascular smooth muscle cells did not affect severity of hypertension, indicating other cellular targets of PGE 2 must mediate this anti-hypertensive effect. Here we report studies examining actions of EP4R in two additional candidate cell lineages: macrophages and kidney epithelial cells, which have both been implicated in hypertension pathogeneses. Cell-specific deletion of EP4R was accomplished by crossing mice bearing a conditional EP4 allele ( EP4 flox ) with mouse lines carrying a LyzM-Cre + transgene expressing in macrophages (MACKOs) or tetracycline-inducible Pax8-rtTA + TetO-Cre + transgene driving expression in renal tubular epithelial cells (RTKOs). Elimination of EP4R from macrophages in MACKOs had minimal effects on baseline BP and salt sensitivity, and responses to chronic Ang II infusion were virtually identical in MACKOs and controls (138±3 vs 133±2 mm Hg; n=14/group). By contrast, absence of EP4R from kidney epithelia in RTKOs caused significant augmentation of Ang II-induced hypertension compared to Controls (average MAP: 145±4 vs. 135±3 mmHg, p=0.03; MAP increase from baseline: 31±2 vs. 20±3 mmHg, p=0.02). The increased severity of hypertension in RTKOs was associated with exaggerated cardiac hypertrophy relative to controls (heart:body weight ratio 8.6±1.5 vs. 7.3±1.2 mg/g; p=0.03). Our findings suggest that kidney epithelial cells, but not macrophages, are critical targets of PGE 2 acting via EP4R to oppose the development of hypertension. As collecting duct is the major site of EP4R expression in renal epithelia, this may reflect actions of EP4R to modulate key sodium transporters in this nephron segment.

Abstract 42: AT1 Angiotensin Receptors in Principal Cells of the Collecting Duct Have Minimal Impact on Blood Pressure and the Development of Hypertension.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Daian Chen ◽  
Johannes Stegbauer ◽  
Matthew A. Sparks ◽  
Donald Kohan ◽  
Susan B. Gurley ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Collecting Duct ◽  
Weight Ratio ◽  
Angiotensin Receptors ◽  
Mrna Levels ◽  
Ang Ii ◽  
Mouse Line ◽  
Dietary Salt ◽  
Transgenic Mouse Line

The main actions of the renin angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT 1 R). The major murine AT 1 R isoform, AT 1A is highly expressed in epithelial cells throughout the nephron, including the collecting duct (CD). The CD consists of two cell types, principal (PC) and intercalated cells (IC) with distinct functions. Activation of AT 1 R in PC stimulates solute reabsorption in the CD by increasing the activity of epithelial sodium channels. To examine the role of the AT 1A R in the PC to BP regulation and the development of hypertension in vivo , we generated inbred 129SvEv mice with cell-specific deletion of AT 1A R in PC (PC-KO, n=6). AQP2-Cre transgenic mouse line was used to excise the floxed Agtr1a allele in PC. mTmG reporter mouse line was used to confirm specific expression of AQP2-Cre transgene in PC, and found the pattern of expression to be predominantly in medullary CD. Using RT-PCR, mRNA levels for AT 1A R were reduced by ≈50% in the inner medulla of PC-KO mice ( P <0.05), but unaffected in cortex. Baseline BP measured by radiotelemetry was similar between PC-KO (122±1.6 mm Hg) and controls (122±1.6 mm Hg). During one week of feeding a low salt (<0.002% NaCl) diet, MAP fell significantly (P<0.05) and to a similar extent in both groups, (PC-KO: 116±1 mm Hg; Controls: 117±2 mm Hg). High salt (6% NaCl) diet increased BP (P<0.01), but was not different between groups (PC-KO: 129±2 mm Hg; Controls: 131±2 mm Hg). Finally, we induced hypertension with chronic infusion of Ang II (1000 ng/kg/min) by osmotic mini-pumps. During the initial phase (days 1-8), there was a modest but significant attenuation of hypertension in PC-KO (167±7 mm Hg) compared to controls (178±3 mm Hg, P<0.001). However, by day 9 levels of BP were indistinguishable between groups and there was no difference in BP in the later phase (days 9-14) of hypertension (PC-KO: 175±12 mm Hg; Controls: 177±7 mm Hg). Heart to body weight ratio after Ang II infusion was not different between groups. In summary, AT 1A R in PC of the medullary CD have little influence on BP, adaptation to changes in dietary salt intake or development of hypertension. We suggest that other mediators, such as aldosterone, may have a more important role to influence sodium handling in this nephron segment.

scholarly journals Lymphocyte responses exacerbate angiotensin II-dependent hypertension

2010 ◽  
Vol 298 (4) ◽  
pp. R1089-R1097 ◽  
Author(s):  
Steven D. Crowley ◽  
Young-Soo Song ◽  
Eugene E. Lin ◽  
Robert Griffiths ◽  
Hyung-Suk Kim ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Sodium Excretion ◽  
Kidney Injury ◽  
Scid Mice ◽  
Prostaglandin E ◽  
Ang Ii ◽  
Blood Pressure Elevation ◽  
Cox 2 ◽  
Lymphocyte Responses

Activation of the immune system by ANG II contributes to the pathogenesis of hypertension, and pharmacological suppression of lymphocyte responses can ameliorate hypertensive end-organ damage. Therefore, to examine the mechanisms through which lymphocytes mediate blood pressure elevation, we studied ANG II-dependent hypertension in scid mice lacking lymphocyte responses and wild-type controls. Scid mice had a blunted hypertensive response to chronic ANG II infusion and accordingly developed less cardiac hypertrophy. Moreover, lymphocyte deficiency led to significant reductions in heart and kidney injury following 4 wk of angiotensin. The muted hypertensive response in the scid mice was associated with increased sodium excretion, urine volumes, and weight loss beginning on day 5 of angiotensin infusion. To explore the mechanisms underlying alterations in blood pressure and renal sodium handling, we measured gene expression for vasoactive mediators in the kidney after 4 wk of ANG II administration. Scid mice and controls had similar renal expression for interferon-γ, interleukin-1β, and interleukin-6. By contrast, lymphocyte deficiency (i.e., scid mice) during ANG II infusion led to upregulation of tumor necrosis factor-α, endothelial nitric oxide synthase (eNOS), and cyclooxygenase-2 (COX-2) in the kidney. In turn, this enhanced eNOS and COX-2 expression in the scid kidneys was associated with exaggerated renal generation of nitric oxide, prostaglandin E2, and prostacyclin, all of which promote natriuresis. Thus, the absence of lymphocyte activity protects from hypertension by allowing blood pressure-induced sodium excretion, possibly via stimulation of eNOS- and COX-2-dependent pathways.

Abstract 114: K+ Rich Diet During Angiotensin II Hypertension Reduces Renal Na-Cl Cotransporter and Phosphorylation, but Not Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Luciana C Veiras ◽  
Jiyang Han ◽  
Donna L Ralph ◽  
Alicia A McDonough
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Weight Ratio ◽  
Distal Tubule ◽  
Reduce Blood Pressure ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
K Secretion ◽  
Pressure Natriuresis

During Ang II hypertension distal tubule Na-Cl Cotransporter (NCC) abundance and its activating phosphorylation (NCCp), as well as Epithelial Na+ channels (ENaC) abundance and activating cleavage are increased 1.5-3 fold. Fasting plasma [K+] is significantly lower in Ang II hypertension (3.3 ± 0.1 mM) versus controls (4.0 ± 0.1 mM), likely secondary to ENaC stimulation driving K+ secretion. The aim of this study was to test the hypothesis that doubling dietary K+ intake during Ang II infusion will lower NCC and NCCp abundance to increase Na+ delivery to ENaC to drive K+ excretion and reduce blood pressure. Methods: Male Sprague Dawley rats (225-250 g; n= 7-9/group) were treated over 2 weeks: 1) Control 1% K diet fed (C1K); 2) Ang II infused (400 ng/kg/min) 1% K diet fed (A1K); or 3) Ang II infused 2% K diet fed (A2K). Blood pressure (BP) was determined by tail cuff, electrolytes by flame photometry and transporters’ abundance by immunoblot of cortical homogenates. Results: As previously reported, Ang II infusion increased systolic BP (from 132 ± 5 to 197 ± 4 mmHg), urine volume (UV, 2.4 fold), urine Na+ (UNaV, 1.3 fold), heart /body weight ratio (1.23 fold) and clearance of endogenous Li+ (CLi, measures fluid volume leaving the proximal tubule, from 0.26 ± 0.02 to 0.51 ± 0.01 ml/min/kg) all evidence for pressure natriuresis. A2K rats exhibited normal plasma [K+] (4.6 ± 0.1 mM, unfasted), doubled urine K+ (UKV, from 0.20 to 0.44 mmol/hr), and increased CLi (to 0.8 ± 0.1 ml/min/kg) but UV, UNaV, cardiac hypertrophy and BP were unchanged versus the A1K group. As expected, NCC, NCCpS71 and NCCpT53 abundance increased in the A1K group to 1.5 ± 0.1, 2.9 ± 0.5 and 2.8 ± 0.4 fold versus C1K, respectively. As predicted by our hypothesis, when dietary K+ was doubled (A2K), Ang II infusion did not activate NCC, NCCpS71 nor NCCpT53 (0.91 ± 0.04, 1.3 ± 0.1 and 1.6 ± 0.2 fold versus C1K, respectively). ENaC subunit abundance and cleavage increased 1.5 to 3 fold in both A1K and A2K groups; ROMK was unaffected by Ang II or dietary K. In conclusion, evidence is presented that stimulation of NCC during Ang II hypertension is secondary to K+ deficiency driven by ENaC stimulation since doubling dietary K+ prevents the activation. The results also indicate that elevation in BP is independent of NCC activation

Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure

1992 ◽  
Vol 262 (6) ◽  
pp. E763-E778 ◽  
Author(s):  
I. A. Reid
Keyword(s):  
Blood Pressure ◽  
Nervous System ◽  
Sympathetic Nervous System ◽  
Blood Pressure Control ◽  
Cardiovascular Responses ◽  
Pressure Control ◽  
Ang Ii ◽  
Arterial Blood ◽  
Baroreceptor Reflexes ◽  
Sympathetic Nervous

The renin-angiotensin system plays an important role in the regulation of arterial blood pressure and in the development of some forms of clinical and experimental hypertension. It is an important blood pressure control system in its own right but also interacts extensively with other blood pressure control systems, including the sympathetic nervous system and the baroreceptor reflexes. Angiotensin (ANG) II exerts several actions on the sympathetic nervous system. These include a central action to increase sympathetic outflow, stimulatory effects on sympathetic ganglia and the adrenal medulla, and actions at sympathetic nerve endings that serve to facilitate sympathetic neurotransmission. ANG II also interacts with baroreceptor reflexes. For example, it acts centrally to modulate the baroreflex control of heart rate, and this accounts for its ability to increase blood pressure without causing a reflex bradycardia. The physiological significance of these actions of ANG II is not fully understood. Most evidence indicates that the actions of ANG to enhance sympathetic activity do not contribute significantly to the pressor response to exogenous ANG II. On the other hand, there is considerable evidence that the actions of endogenous ANG II on the sympathetic nervous system enhance the cardiovascular responses elicited by activation of the sympathetic nervous system.

scholarly journals Genetic deletion of AT1a receptors attenuates intracellular accumulation of ANG II in the kidney of AT1a receptor-deficient mice

2007 ◽  
Vol 293 (2) ◽  
pp. F586-F593 ◽  
Author(s):  
Xiao C. Li ◽  
L. Gabriel Navar ◽  
Yuan Shao ◽  
Jia L. Zhuo
Keyword(s):  
Blood Pressure ◽  
Sodium Excretion ◽  
Rat Kidney ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
Ang Ii ◽  
Wild Type ◽  
Deficient Mice

We and others have previously shown that high levels of ANG II are accumulated in the rat kidney via a type 1 (AT1) receptor-mediated mechanism, but it is not known which AT1 receptor is involved in this process in rodents. We tested the hypothesis that AT1a receptor-deficient mice (Agtr1a−/−) are unable to accumulate ANG II intracellularly in the kidney because of the absence of AT1a receptor-mediated endocytosis. Adult male wild-type (Agtr1a+/+), heterozygous (Agtr1a+/−), and Agtr1a−/− were treated with vehicle, ANG II (40 ng/min ip via osmotic minipump), or ANG II plus the AT1 antagonist losartan (10 mg·kg−1·day−1 po) for 2 wk. In wild-type mice, ANG II induced hypertension (168 ± 4 vs. 113 ± 3 mmHg, P < 0.001), increased kidney-to-body weight ratio ( P < 0.01), caused pressure natriuresis ( P < 0.05), and elevated plasma and whole kidney ANG II levels ( P < 0.001). Concurrent administration of ANG II with losartan attenuated these responses to ANG II. In contrast, Agtr1a−/− mice had lower basal systolic pressures ( P < 0.001), smaller kidneys with much fewer AT1b receptors ( P < 0.001), higher basal 24-h urinary sodium excretion ( P < 0.01), as well as basal plasma and whole kidney ANG II levels ( P < 0.01). However, intracellular ANG II levels in the kidney were lower in Agtr1a−/− mice. In Agtr1a−/− mice, ANG II slightly increased systolic pressure ( P < 0.05) but had no effect on the kidney weight, urinary sodium excretion, and whole kidney ANG II levels. Losartan restored systolic pressure to basal levels and decreased whole kidney ANG II levels by ∼20% ( P < 0.05). These results demonstrate a predominant role of AT1a receptors in blood pressure regulation and in the renal responses to long-term ANG II administration, that AT1b receptors may play a limited role in blood pressure control and mediating intrarenal ANG II accumulation in the absence of AT1a receptors.

Abstract 208: Action of Multifaceted Microglia on Blood Pressure Control

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
You Li ◽  
Liang Li ◽  
Zhiying Shan ◽  
Kenneth E Bernstein ◽  
Xiao Shen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Neuronal Plasticity ◽  
Microglial Activation ◽  
Myeloid Cell ◽  
Mannose Receptor ◽  
Pressure Control ◽  
Ang Ii ◽  
Differentiation Markers ◽  
Microglial Cell Line ◽  
Blood Pressure Responses

Microglia are the resident surveillance cells in the CNS, and are involved in shaping neuronal plasticity. Previous studies show that hypertension is associated with neuroinflammation. Interference of neuroinflammation by targeting microglia can inhibit or attenuate hypertension. To investigate the phenotypic changes of microglia during hypertension, we compared the profiles of microglia dissociated from normotensive and Ang II-induced hypertensive mice by flow cytometry. We found significant increases in the expression of CD89 (76%), CCR7 (52%), IFNγR (150%), MHC II (85%), CCR2 (51%), IL-4R (164%), mannose receptor (61%) and CD36 (60%) in Ang II microglia compared to the controls. To understand whether the microglial activation has a direct effect on blood pressure, we utilized microglia adoptive transfer strategy via intracerebroventricular (ICV) injection and then examined the blood pressure responses. Mouse microglial cell line, N9, was stimulated in groups as follows: 1) medium control, 2) 10 ng/ml LPS, 3)10 ng/ml LPS + 100 μM minocycline. After 6 hr treatment, half a million N9 cells were transferred into mice via ICV injection. Twenty-four hr later, the recipient mice were anesthetized, cannulated and positioned on the stereotaxic frame. The baseline blood pressure and heart rates were similar among groups (82±2 mmHg, 328±12.8 bpm). However, when we injected Ang II (50 ng in 1μl, ICV), there was a significant prolonged response in the recipient mice transferred with LPS-primed microglia compared to the ones receiving naïve controls (LPS 817±170 sec vs. control 475±70 sec; P<0.05 by unpaired T-test). This increase was fully abolished by co-incubation with minocycline, an inhibitor for microglial activation (LPS+minocycline 507±33 sec). There were no differences observed in pressure magnitude to ICV Ang II across the groups (11±2 mmHg). These data suggest that activated microglia alter neuronal plasticity and potentiate the neuronal responses to Ang II challenge. Taken together, microglial cells are activated, manifested by up-regulation of myeloid cell differentiation markers during hypertension, and then participate in the modulation of blood pressure.

scholarly journals Differential expression and targeting of endogenous Arf1 and Arf6 small GTPases in kidney epithelial cells in situ

2004 ◽  
Vol 286 (4) ◽  
pp. C768-C778 ◽  
Author(s):  
Jaafar El Annan ◽  
Dennis Brown ◽  
Sylvie Breton ◽  
Sylvain Bourgoin ◽  
Dennis A. Ausiello ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Western Blotting ◽  
Collecting Duct ◽  
Small Gtpases ◽  
Renal Physiology ◽  
Principal Cells ◽  
Arf Gtpases ◽  
Kidney Epithelial Cells

ADP-ribosylation factors (Arfs) are small GTPases that regulate vesicular trafficking in exo- and endocytotic pathways. As a first step in understanding the role of Arfs in renal physiology, immunocytochemistry and Western blotting were performed to characterize the expression and targeting of Arf1 and Arf6 in epithelial cells in situ. Arf1 and Arf6 were associated with apical membranes and subapical vesicles in proximal tubules, where they colocalized with megalin. Arf1 was also apically expressed in the distal tubule, connecting segment, and collecting duct (CD). Arf1 was abundant in intercalated cells (IC) and colocalized with V-ATPase in A-IC (apical) and B-IC (apical and/or basolateral). In contrast, Arf6 was associated exclusively with basolateral membranes and vesicles in the CD. In the medulla, basolateral Arf6 was detectable mainly in A-IC. Expression in principal cells became weaker throughout the outer medulla, and Arf6 was not detectable in principal cells in the inner medulla. In some kidney epithelial cells Arf1 but not Arf6 was also targeted to a perinuclear patch, where it colocalized with TGN38, a marker of the trans-Golgi network. Quantitative Western blotting showed that expression of endogenous Arf1 was 26–180 times higher than Arf6. These data indicate that Arf GTPases are expressed and targeted in a cell- and membrane-specific pattern in kidney epithelial cells in situ. The results provide a framework on which to base and interpret future studies on the role of Arf GTPases in the multitude of cellular trafficking events that occur in renal tubular epithelial cells.

scholarly journals Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II–Induced Hypertension in Mice

Hypertension ◽  
2020 ◽  
Author(s):  
Ye Feng ◽  
Kexin Peng ◽  
Renfei Luo ◽  
Fei Wang ◽  
Tianxin Yang
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Collecting Duct ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Short Circuit Current ◽  
Duct Cell ◽  
Ang Ii ◽  
Cortical Collecting Duct ◽  
Induced Hypertension

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

scholarly journals Highly tamoxifen-inducible principal cell-specific Cre mice with complete fidelity in cell specificity and no leakiness

2018 ◽  
Vol 314 (4) ◽  
pp. F572-F583 ◽  
Author(s):  
Lihe Chen ◽  
Chao Gao ◽  
Long Zhang ◽  
Ye Zhang ◽  
Enuo Chen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Target Genes ◽  
Collecting Duct ◽  
Pressure Control ◽  
Lineage Tracing ◽  
Principal Cell ◽  
Driver Gene ◽  
Cell Markers ◽  
Adult Mice ◽  
Cell Specificity

An ideal inducible system should be cell specific and have absolutely no background recombination without induction (i.e., no leakiness), a high recombination rate after induction, and complete fidelity in cell specificity (i.e., restricted recombination exclusively in cells where the driver gene is expressed). However, such an ideal mouse model remains unavailable for collecting duct research. Here, we report a mouse model that meets these criteria. In this model, a cassette expressing ERT2CreERT2 ( ECE) is inserted at the ATG of the endogenous Aqp2 locus to disrupt Aqp2 function and to express ECE under the control of the Aqp2 promoter. The resulting allele is named Aqp2ECE. There was no indication of a significant impact of disruption of a copy of Aqp2 on renal function and blood pressure control in adult Aqp2ECE/+ heterozygotes. Without tamoxifen, Aqp2ECE did not activate a Cre-dependent red fluorescence protein (RFP) reporter in adult kidneys. A single injection of tamoxifen (2 mg) to adult mice enabled Aqp2ECE to induce robust RFP expression in the whole kidney 24 h postinjection, with the highest recombination efficiency of 95% in the inner medulla. All RFP-labeled cells expressed principal cell markers (Aqp2 and Aqp3), but not intercalated cell markers (V-ATPase B1B2, and carbonic anhydrase II). Hence, Aqp2ECE confers principal cell-specific tamoxifen-inducible recombination with absolutely no leakiness, high inducibility, and complete fidelity in cell specificity, which should be an important tool for temporospatial control of target genes in the principal cells and for Aqp2+ lineage tracing in adult mice.

Salt-sensitive hypertension develops after transient induction of ANG II-dependent hypertension in Cyp1a1-Ren2 transgenic rats

2005 ◽  
Vol 288 (4) ◽  
pp. F810-F815 ◽  
Author(s):  
Laura L. Howard ◽  
Matthew E. Patterson ◽  
John J. Mullins ◽  
Kenneth D. Mitchell
Keyword(s):  
Blood Pressure ◽  
Renal Plasma Flow ◽  
Systolic Pressure ◽  
High Salt ◽  
Ang Ii ◽  
Transgenic Rats ◽  
High Salt Diet ◽  
Blood Pressure Elevation ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

Transient exposure to ANG II results in the development of salt-sensitive hypertension in rats. This study was performed to determine whether a transient hypertensive episode can induce salt-sensitive hypertension in transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name TGR(Cyp1a1-Ren2)]. Systolic blood pressures were measured in conscious male Cyp1a1-Ren2 rats ( n = 6) during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.15%, wt/wt), for 14 days. Systolic pressure increased from 135 ± 5 to 233 ± 7 mmHg by day 14. I3C administration was terminated and blood pressure returned to normal levels (137 ± 5 mmHg) within 10 days. Subsequently, the rats were placed on a high-salt diet (8% NaCl) for 10 days. Systolic pressure increased by 34 ± 2 mmHg throughout 10 days of the high-salt diet. Neither glomerular filtration rate nor renal plasma flow was altered in Cyp1a1-Ren2 rats with salt-sensitive hypertension. In a separate group of male Cyp1a1-Ren2 rats ( n = 6) transiently induced with 0.15% I3C for 14 days, administration of the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, 2 mM) attenuated the increase in systolic pressure induced by high salt. Systolic pressure increased by only 11 ± 1 mmHg throughout 8 days of a high-salt diet and tempol administration. Thus transient induction of ANG II-dependent hypertension via activation of the Cyp1a1-Ren2 transgene induces salt-sensitive hypertension in these transgenic rats. The attenuation by tempol of the high salt-induced blood pressure elevation indicates that ANG II-induced production of superoxide anion contributes to the development of salt-sensitive hypertension after transient induction of ANG II-dependent hypertension.

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