Abstract MP09: Adrenal-specific Deletion of TASK Channels Evokes Normal-Renin Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Nick A Guagliardo ◽  
Thu H Le ◽  
Douglas A Bayliss ◽  
David T Breault ◽  
Paula Q Barrett
Keyword(s):  
Blood Pressure ◽  
Radio Telemetry ◽  
Plasma Renin ◽  
Zona Glomerulosa ◽  
Angiotensin Ii Receptor ◽  
Task Channels ◽  
The Difference ◽  
Angiotensin Ii Receptor Blockade ◽  
Design And Methods ◽  
Specific Deletion

Objectives: Dysregulation of aldosterone (Aldo) production is predicted to evoke major features of idiopathic primary hyperaldosteronism (IHA): low renin, elevated blood pressure and suppressed control by high Na. We have previously demonstrated in mice that global deletion of background TWIK-related acid-sensitive K (TASK) channels (TASK-1, TASK-3) effect a ~20mV decrease in the membrane potential of Zona Glomerulosa (ZG) cells to produce frank autonomous overproduction of Aldo, low renin, and hypertension (HT), mimicking the salient features of human IHA. In the current study, we ask if specific deletion of TASK channels in ZG cells is sufficient to produce hyperaldosteronism and the predicted sequela or if extra-adrenal deletion of TASK channels is required. Design and Methods: We generated a trigenic mouse-line ( AS +Cre ::TASK-1 ff ::TASK-3 ff , zT1T3KO) in which TASK-1 and TASK-3 subunits were specifically deleted in ZG cells. The renin-angiotensin-aldosterone system (RAAS) was evaluated in mice housed in metabolic cages and stabilized on various salt diets. Urinary Aldo concentration was measured and normalized to creatinine (ng Aldo/mg creatinine; 24 hr. urine collection). Blood pressure was recorded in conscious, freely moving mice using radio telemetry, and plasma renin concentration was measured from tail vein sampling. Results: Overproduction of aldosterone on normal-salt diet (0.3% Na) was modest in zT1T3KO mice compared to littermate controls (WT; WT 9.4; KO 11.8 ng/mg, 1.25-fold). Suppression of Aldo production by high-salt (2% Na) was blunted, exaggerating the difference in Aldo production between genotypes (WT 3.0; KO 7.4 ng/mg, 2.43-fold). zT1T3KO mice were hypertensive (mean MAP: WT 103.5; KO 113.1 mmHg), yet renin levels remained normal. Neither hyperaldosteronism nor HT could be corrected by angiotensin II receptor blockade, suggesting overproduction of Aldo and HT are independent of RAAS. Conclusions: Limiting TASK deletion to ZG cells results in normal renin HT driven by modest autonomous hyperaldosteronism, a stark contrast to the phenotypic features of IHA recapitulated by global TASK deletion. Together these mouse models provide insight into the role of ZG- vs extra-adrenal-dysfunction in the pathology of IHA.

scholarly journals RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN PATIENTS WITH ABDOMINAL OBESITY AND ARTERIAL HYPERTENSION

2013 ◽  
Vol 19 (5) ◽  
pp. 389-396 ◽  
Author(s):  
E. A. Bazhenova ◽  
O. D. Belyaeva ◽  
A. V. Berezina ◽  
T. L. Karonova ◽  
D. A. Kolodina ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Obese Patients ◽  
Renin Angiotensin Aldosterone System ◽  
Plasma Aldosterone Concentration ◽  
Renin Angiotensin ◽  
Primary Disorder ◽  
Per Se ◽  
Design And Methods

Objective. The activity of renin-angiotensin-aldosterone system (RAAS) is increased in patients with ab-dominal obesity (AO). However, till present time it is unclear whether RAAS activation or hypertension (HTN) found in 50 % patients is the primary disorder.Design and methods. We have studied plasma renin activity (PRA), plasma aldosterone concentration (PAC), their ratio PAC/PRA in patients with AO and related HTN and in subjects without AO.Results. PRA was higher in patients with AO versus people without obesity (2,5 ± 0,2 and 1,7 ± 0,7 ng/ml/hr, p = 0,013), there was a tendency to the reduction of the ratio PAC/PRA in obese patients (14,6 ± 0,9 and 19,7 ± 3,3, p = 0,08). In the subgroup of patients with AO and HTN the PRA was higher, and the ratio PAC/PRA was lower than in obese patients without HTN (PRA: 3,3 ± 0,4 and 1,7±0,2 ng/ml/hr, p = 0,005; PAC/PRA: 11,4 ± 1,1 and 17,4 ± 1,4, p < 0,0001). PRA and systolic blood pressure positively correlated. In patients with morbid obesity (3 degree according to the WHO classiication) obesity may play a signiicant role in the increase of RAAS activity, especially in the absence of concomitant HTN. The ratio PAC/PRA in over weight patients with AO was higher than in patients with AO and body mass index ? 30,0 kg/m (17,2 ± 1,7 and 12,5 ± 1,0 kg/m, p = 0,04). PRA was higher only in patients with AO and co-existing hypertension (3,4 ± 0,7 and 1,1 ± 0,2 ng/ml/hr, p = 0,04).Conclusions. RAAS activity is increased in patients with AO, also due to the co-existing HTN. However, in the absence of elevated blood pressure obesity per se may play a signiicant role in RAAS hyperactivity.

Abstract 308: Nephron Specific Deletion Of Angiotensinogen Modulates Blood Pressure

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Matias Calquin ◽  
Shuping Wang ◽  
Fumio Niimura ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Proximal Tubule ◽  
Urine Volume ◽  
Plasma Renin ◽  
Urine Osmolality ◽  
Metabolic Balance ◽  
Salt Diet ◽  
Plasma Renin Concentration ◽  
Specific Deletion

It is unknown if intrarenal generation of angiotensinogen (AGT) is important in blood pressure (BP) regulation. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, while proximal tubule-specific deletion of AGT using the KAP promoter-Cre transgene did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron-wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP flanked AGT alleles to achieve nephron-specific AGT disruption after doxycycline induction. Adult Pax8-rtTA/LC-1/floxed AGT mice at 3 months of age were treated with doxycycline 2 mg/ml in drinking water for 11 days and studied 4 weeks after treatment. Blood pressure (recorded via telemetry) and metabolic balance studies were determined during 5 days of normal, high and low Na diets. Compared to controls, AGT knockout (KO) mice demonstrated significantly lower systolic, diastolic, and mean BPs on all three diets (N=4 each group). The BP reduction was most evident on a low Na diet (mean BP 107 ± 2 mmHg in controls and 88 ± 13 mmHg in AGT KO). Plasma renin concentration was higher in the AGT KO mice as compared to controls on all three diets. There were no detectable differences in weight, urine volume, urine osmolality or urine Na excretion between the controls and KO mice on all three diets, however due to variability, small differences in these parameters may not have been detected. Taken together, these data suggest that nephron AGT may contribute to BP regulation and this is most evident during low Na intake.

Mechanisms underlying the cardiovascular responses to intrathecal vasopressin administration in rats

1989 ◽  
Vol 67 (4) ◽  
pp. 269-275 ◽  
Author(s):  
Colleen L. Riphagen ◽  
Quentin J. Pittman
Keyword(s):  
Blood Pressure ◽  
Spinal Cord ◽  
Heart Rate ◽  
Plasma Renin ◽  
Cardiovascular Responses ◽  
Blocking Agent ◽  
Intrathecal Administration ◽  
Receptor Blockade ◽  
Angiotensin Ii Receptor ◽  
Pressor Responses

Vasopressinergic pathways within the spinal cord have been implicated in the control of cardiovascular function. This study was undertaken to determine the mechanisms whereby intrathecally administered arginine vasopressin (AVP) increases blood pressure and heart rate in anesthetized rats. The cardiovascular responses to intrathecal AVP administration were significantly attenuated after intravenous administration of the ganglionic blocking agent, chlorisondamine chloride, as were the pressor responses following α-adrenergic receptor blockade with phentolamine and the heart rate responses following β-receptor blockade with propranolol. Intrathecal administration of the V1 vasopressin receptor antagonist d(CH2)5Tyr(Me)AVP completely blocked the cardiovascular responses to intrathecal AVP injections, but did not significantly alter the responses to intrathecal substance P injections. There was no evidence for the involvement of the rennin–angiotensin system in the pressor responses to intrathecal AVP, as (i) an angiotensin II receptor blocking agent, [Sar1, Val5, Ala8]angiotensin, failed to significantly alter the responses to intrathecal AVP, and (ii) plasma renin levels did not change following administration of the peptide. Intrathecal injections of [3H]AVP suggest that only small amounts of the peptide may cross into the plasma during the time in which the cardiovascular variables are changing. These data provide evidence that intrathecally administered AVP discretely activates the sympathetic outflow to the heart and vasculature, and confirm the neurally mediated nature of the response.Key words: blood pressure, spinal cord, peptides, autonomic nervous system, neurotransmitter.

Abstract 014: Collecting Duct Specific Deletion of the (Pro)renin Receptor Modulates ENaC Expression

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Kai Song ◽  
Nikita Abraham ◽  
Shuping Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Cre Recombinase ◽  
Protein Isoforms ◽  
Ang Ii ◽  
Renal Tubular ◽  
Renal Expression ◽  
Specific Deletion

The renal tubular (pro)renin receptor (PRR) has been shown to modulate water balance, blood pressure and Na + homeostasis. We recently reported that inducible nephron wide deletion of the PRR results in Na + wasting, reduced epithelial Na + channel (ENaC) expression in the kidney and attenuated hypertensive response to angiotensin-II (Ang-II) infusion. In this study, we examined the effects of PRR deletion in collecting duct (CD) specific mouse models targeting either the principal cells (PC) or intercalated cells (IC). PC-specific PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring AQP-2 Cre recombinase. Compared to floxed mice, PC specific KO PRR mice had no differences in PRR immunostaining but had 50% reduction in PRR mRNA in micro-dissected cortical CDs. No differences in blood pressure were observed between the two groups at baseline or following Ang-II infusion at 600 ng/kg/min. Similarly, plasma renin concentration and renal expression of ENaC protein isoforms were comparable between the two groups. To achieve IC-specific PRR deletion, floxed PRR mice were bred with mice expressing B-1 Cre recombinase. Compared to floxed controls, IC-specific PRR KO mice were smaller (KO body weight: 5.9 ± 1.3 g vs controls: 11.1± 1.2 g) and did not survive beyond 30 days after birth. IC-specific PRR KO mice also demonstrated marked reduction in renal medullary PRR immunostaining along with decreased renal expression of ENaC-α protein (50% reduction compared to controls), similar to the findings in nephron wide deletion of PRR. Taken together, these findings suggest that IC specific deletion of PRR but not PC-specific deletion modulates renal ENaC expression. Further studies evaluating ENaC activity in isolated cortical CDs from PC and IC specific PRR KO mice will help delineate the functional role of CD PRR in Na + homeostasis.

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