Increased blood pressure in transgenic mice expressing both human renin and angiotensinogen in the renal proximal tubule

2004 ◽  
Vol 286 (5) ◽  
pp. F965-F971 ◽  
Author(s):  
Julie L. Lavoie ◽  
Kristy D. Lake-Bruse ◽  
Curt D. Sigmund
Keyword(s):  
Blood Pressure ◽  
Arterial Pressure ◽  
Proximal Tubule ◽  
Renin Angiotensin System ◽  
Renal Proximal Tubule ◽  
Plasma Testosterone ◽  
Angiotensin System ◽  
Testosterone Treatment ◽  
Renin Angiotensin ◽  
Human Renin

The purpose of this study was to evaluate the physiological significance of a tissue renin-angiotensin system in the proximal tubule of the kidney. To accomplish this, we produced mice that express human renin (hREN) under the control of the kidney androgen-regulated promoter (KAP), which is androgen responsive. One of the lines expressed the hREN transgene primarily in the kidney. Renal expression of the transgene was undetectable in females but could be induced by testosterone treatment. Because the renin-angiotensin system is species specific, we bred KAP2-hREN mice with the mice expressing human angiotensinogen under the same promoter (KAP-hAGT) to produce offspring that expressed both transgenes. We measured mean arterial blood pressure (MAP) in the carotid artery of double-transgenic and control mice using radiotelemetry. Double-transgenic female mice had a normal baseline MAP (116 ± 4 mmHg, n = 8), which increased by 15 mmHg after 2 wk of testosterone treatment, and returned to baseline after elimination of the testosterone pellet. The change in arterial pressure paralleled the change in plasma testosterone. There was no MAP change in testosterone-treated control littermates. We conclude that dual production of renin and angiotensinogen in the renal proximal tubule can result in a systemic increase in arterial pressure. These data support a role for a tissue-specific renin-angiotensin system in the renal proximal tubule that contributes to the regulation of systemic blood pressure.

Abstract 356: A Role for Renal Proximal Tubule Sodium Bicarbonate Cotransporter SLC4A5 in Salt-Sensitivity of Blood Pressure

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Julia M Carlson ◽  
John J Gildea ◽  
Helen E McGrath ◽  
Robin A Felder
Keyword(s):  
Sodium Bicarbonate ◽  
Proximal Tubule ◽  
Mrna Expression ◽  
Cell Lines ◽  
Renin Angiotensin System ◽  
Salt Sensitivity ◽  
Renal Proximal Tubule ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Homozygous Variant

SLC4A5 is a sodium-bicarbonate co-transporter involved with sodium homeostasis. Based on unpublished data, two SLC4A5 single nucleotide polymorphisms (SNPs rs1017783 and rs7571842) have been highly associated with an individual’s salt-sensitivity status. Since the renal proximal tubule (RPT) regulates a large percentage of renal sodium transport, we investigated whether SLC4A5 was present in this nephron segment. Using confocal immunofluorescence microscopy, we found expression of SLC4A5 in human RPT cell plasma membrane and intracellular membrane vesicles. We then examined the physiologic implications of the SLC4A5 SNPs in human RPT cells. Using immunoblotting and RT-PCR, we found no significant differences in basal SLC4A5 expression in RPT cells between individuals that are homozygous variant at both SNPs and individuals that are wild-type (WT) for both alleles. Stimulation of the dopaminergic system with 1μM fenoldopam, or the renin-angiotensin system with 10 nM angiotensin II or 10 nM angiotensin III (n=18 per treatment) over 3 and 24 hours did not significantly alter SLC4A5 protein or 24 hour mRNA expression. These data indicate that SLC4A5 is not directly regulated by either the renal dopaminergic or renin-angiotensin system. However, 24 hour stimulation with the sodium ionophore monensin (MON, 1μM) significantly increased overall mRNA expression of SLC4A5 by 182±0.098% over vehicle (VEH) (ΔCq VEH=0.283±0.035; n=18, p<0.001). There was also a significant increase in SLC4A5 mRNA in three cell lines homozygous variant for both alleles compared to three WT cell lines following MON treatment at both 3 hours (138±0.10%; ΔCq WT MON = 0.5±0.052; n=9, p<0.05) and 24 hours (161±0.11%; ΔCq WT MON = 0.39±0.066; n=9, p<0.02). Three but not 24 hour stimulation with MON also significantly increased overall expression of SLC4A5 protein (137±0.00041%; RFU VEH=0.0030±0.00022; n=18, p<0.01). MON, by allowing salt to enter a cell, may be activating an enhancer that leads to increased transcription of SLC4A5 mRNA that is more effective in homozygous variant cell lines. These novel observations demonstrate that SNPs located in a non-promoter DNA intron are associated with enhanced promoter activity that is regulated by altered intracellular sodium.

Renin-angiotensin system in hypophysectomized rats. I. Control of blood pressure

1984 ◽  
Vol 246 (1) ◽  
pp. E84-E88
Author(s):  
C. D. Simon ◽  
T. W. Honeyman ◽  
J. C. Fray
Keyword(s):  
Blood Pressure ◽  
Arterial Pressure ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Arterial Blood ◽  
Hormone Administration ◽  
Hypophysectomized Rats

The mechanisms whereby the pituitary gland maintains arterial pressure were investigated in rats. The arterial pressure in hypophysectomized rats was 30 mmHg below normal. Saralasin or captopril caused a further fall of 25 and 30 mmHg, respectively, suggesting that the renin-angiotensin system plays a role in blood pressure maintenance in hypophysectomized rats. Growth hormone administration to hypophysectomized rats increased the arterial pressure, but pretreatment with captopril prevented the effect. Plasma renin activity and basal renin secretion (in vitro) was normal in hypophysectomized rats despite a twofold greater renal renin content. Secretory responsiveness to isoproterenol and calcium omission was lower in hypophysectomized rats. It is concluded that the renin-angiotensin system plays a role in maintaining arterial blood pressure in hypophysectomized rats although the responsiveness of the system may be decreased.

Blood pressure effects of renin inhibition by human renin antiserum in normotensive marmosets

1984 ◽  
Vol 246 (3) ◽  
pp. F309-F316 ◽  
Author(s):  
J. B. Michel ◽  
J. Wood ◽  
K. Hofbauer ◽  
P. Corvol ◽  
J. Menard
Keyword(s):  
Blood Pressure ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Pressure Effects ◽  
Sodium Balance ◽  
New World Monkeys ◽  
Common Marmosets ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Human Renin

The effects on blood pressure of an antiserum against pure human kidney renin were studied in conscious and anesthetized (pentobarbital, 24 mg X kg-1 i.p.) small new world monkeys (common marmosets). The antiserum inhibited the enzymatic activity of renin by 50% in a dilution of 1:45,000 in marmoset and 1:50,000 in human plasma. The antiserum (0.2 ml i.v.) decreased blood pressure in conscious marmosets on normal sodium intake by 15 +/- 5 (SD) mmHg and after salt depletion by 31 +/- 13 mmHg. A converting enzyme inhibitor (teprotide, 2 mg X kg-1 i.v.) induced a comparable fall in blood pressure: -16 +/- 10 and -30 +/- 10 mmHg, respectively. Similar effects were observed on blood pressure of anesthetized marmosets. The correlation between pretreatment plasma renin concentration and the maximum fall in blood pressure was significant and identical for the experiments with antiserum and teprotide. These results demonstrate that antisera against human renin can be used for the specific blockade of the renin-angiotensin system in primates. In normotensive marmosets the renin-angiotensin system participates in the maintenance of blood pressure, to a degree depending on the state of sodium balance.

Neurohumoral mechanisms in acute aortic coarctation in conscious and anesthetized dogs

1983 ◽  
Vol 244 (4) ◽  
pp. H614-H621
Author(s):  
P. L. Whitlow ◽  
R. E. Katholi
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Carotid Sinus ◽  
Renin Angiotensin System ◽  
Sodium Retention ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Anesthetized Dogs ◽  
Blood Pressure Responses

To study the interactions of the renin-angiotensin system, sodium balance, and the sympathetic nervous system in the development of coarctation hypertension, an aortic gradient was created with a pneumatic cuff in 11 chronically instrumented conscious dogs. Significant hypertension associated with a significant rise in plasma renin activity and sodium retention occurred within 48 h. Competitive angiotensin II blockade caused a greater decrease in arterial pressure after coarctation than before coarctation. In contrast, plasma norepinephrine decreased significantly from control levels after coarctation, and alpha-adrenergic blockade with phentolamine caused less of a decrease in arterial pressure than before coarctation. This decrease in sympathetic activity was also accompanied by a decreased blood pressure response to pressor doses of angiotensin II and methoxamine after coarctation. To assess carotid baroreceptor influence on acute coarctation hypertension, aortic blood pressure responses to pressor agents were determined in 12 chlorolose-urethan-anesthetized dogs while carotid sinus pressure was independently varied. Maintaining carotid pressure at control levels after aortic constriction restored blood pressure responses to pressor agents to before-coarctation levels. These results suggest that 1) activation of the renin-angiotensin system and sodium retention contribute to the development of coarctation hypertension, and 2) there is a carotid sinus baroreceptor-mediated decrease in alpha-adrenergic activity with acute coarctation hypertension.

scholarly journals Acute AT1-receptor blockade reverses the hemodynamic and baroreflex impairment in adult sheep exposed to antenatal betamethasone

2010 ◽  
Vol 299 (2) ◽  
pp. H541-H547 ◽  
Author(s):  
Hossam A. Shaltout ◽  
James C. Rose ◽  
Jorge P. Figueroa ◽  
Mark C. Chappell ◽  
Debra I. Diz ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Arterial Pressure ◽  
Low Frequency ◽  
Renin Angiotensin System ◽  
Premature Delivery ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Angiotensin Type

To accelerate lung development and protect neonates from other early developmental problems, synthetic steroids are administered maternally in the third trimester, exposing fetuses that are candidates for premature delivery to them. However, steroid exposure at this point of gestation may lead to elevated blood pressure [mean arterial pressure (MAP)] during adolescence. We hypothesize that fetal exposure to steroids activates the renin-angiotensin system, inducing an elevation in blood pressure and attenuation of baroreflex sensitivity (BRS) that is angiotensin II dependent in early adulthood. To test this hypothesis, fetal sheep were exposed to betamethasone (Beta) or vehicle (control) administered to ewes at day 80 of gestation and delivered at full term. At 1.8 yr of age, male offspring were instrumented for conscious recording of MAP, heart rate, and measurement of BRS [as low-frequency-α, high-frequency-α, sequence (seq) UP, seq DOWN, and seq TOTAL]. Beta-exposed sheep ( n = 6) had higher MAP than control sheep ( n = 5) (93 ± 2 vs. 84 ± 2 mmHg, P < 0.01). Acute blockade of angiotensin type 1 receptors with candesartan (0.3 mg/kg iv) normalized MAP in Beta-exposed sheep (85 ± 4 mmHg), with no effect in control sheep (82 ± 3 mmHg). Before angiotensin type 1 blockade, BRS maximum gain was significantly lower in Beta-exposed vs. control sheep (11 ± 3 vs. 26 ± 3 ms/mmHg, P < 0.0.01). However, 45 min after candesartan injection, BRS was increased in Beta-exposed (21 ± 5 ms/mmHg) and control (35 ± 4 ms/mmHg) sheep. Heart rate variability (HRV) and blood pressure variability (BPV) revealed lower HRV (SD of beat-to-beat interval and root mean square of successive beat-to-beat differences in R-R interval duration) and higher BPV (SD of MAP, systolic arterial pressure in low-frequency range) in Beta-exposed sheep. Candesartan partially restored HRV in Beta-exposed sheep and fully corrected BPV. Thus, in utero exposure to synthetic glucocorticoids causes long-lasting programming of the cardiovascular system via renin-angiotensin system-dependent mechanisms.

Terlipressin Versus  Norepinephrine to Correct Refractory Arterial Hypotension after General Anesthesia in Patients Chronically Treated with Renin-Angiotensin System Inhibitors

2003 ◽  
Vol 98 (6) ◽  
pp. 1338-1344 ◽  
Author(s):  
Gilles Boccara ◽  
Alexandre Ouattara ◽  
Gilles Godet ◽  
Eric Dufresne ◽  
Michèle Bertrand ◽  
...  
Keyword(s):  
Blood Pressure ◽  
General Anesthesia ◽  
Arterial Blood Pressure ◽  
Renin Angiotensin System ◽  
Arterial Hypotension ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Arterial Blood ◽  
Long Term Treatment ◽  
Systolic Arterial Blood Pressure

Background Terlipressin, a precursor that is metabolized to lysine-vasopressin, has been proposed as a drug for treatment of intraoperative arterial hypotension refractory to ephedrine in patients who have received long-term treatment with renin-angiotensin system inhibitors. The authors compared the effectiveness of terlipressin and norepinephrine to correct hypotension in these patients. Methods Among 42 patients scheduled for elective carotid endarterectomy, 20 had arterial hypotension following general anesthesia that was refractory to ephedrine. These patients were the basis of the study. After randomization, they received either 1 mg intravenous terlipressin (n = 10) or norepinephrine infusion (n = 10). Beat-by-beat recordings of systolic arterial blood pressure and heart rate were stored on a computer. The intraoperative maximum and minimum values of blood pressure and heart rate, and the time spent with systolic arterial blood pressure below 90 mmHg and above 160 mmHg, were used as indices of hemodynamic stability. Data are expressed as median (95% confidence interval). Results Terlipressin and norepinephrine corrected arterial hypotension in all cases. However, time spent with systolic arterial blood pressure below 90 mmHg was less in the terlipressin group (0 s [0-120 s] vs. 510 s [120-1011 s]; P &lt; 0.001). Nonresponse to treatment (defined as three boluses of terlipressin or three changes in norepinephrine infusion) occurred in zero and eight cases (P &lt; 0.05), respectively. Conclusions In patients who received long-term treatment with renin-angiotensin system inhibitors, intraoperative refractory arterial hypotension was corrected with both terlipressin and norepinephrine. However, terlipressin was more rapidly effective for maintaining normal systolic arterial blood pressure during general anesthesia.

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