Abstract P198: Biphasic And Sex-dependent Roles Of The Prorenin Receptor In The Rostral Ventrolateral Nucleus In Mice Subjected To Deoxycorticosterone Acetate-salt Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Pablo Nakagawa ◽  
Daniel Brozoski ◽  
Natalia M Mathieu ◽  
Ko-Ting Lu ◽  
Javier Gomez ◽  
...  
Keyword(s):  
Sodium Excretion ◽  
Pressor Response ◽  
Renin Angiotensin System ◽  
Urinary Sodium Excretion ◽  
Protective Role ◽  
Salt Treatment ◽  
Deoxycorticosterone Acetate ◽  
Prorenin Receptor ◽  
Ventrolateral Nucleus ◽  
Salt Hypertension

The brain renin angiotensin system (RAS) regulates blood pressure (BP) and autonomic function. However, it remains unclear how and where angiotensin II (Ang II) is generated in conditions eliciting brain RAS overactivation including deoxycorticosterone acetate (DOCA)-salt hypertension (HT). In several tissues, the activation of prorenin requires its binding to the prorenin receptor (PRR). New evidence from this study indicates that prorenin and PRR are co-expressed in the proximity to the rostral ventrolateral nucleus (RVL), an anatomical brain region that controls sympathetic nerve activity. Therefore, we hypothesized that selective ablation of PRR targeting the RVL attenuates BP increase due to DOCA-salt. PRR ablation was targeted to the RVL by stereotactic microinjections of adeno-associated virus (AAV) expressing Cre recombinase-mCherry in PRR-flox mice (PRR RVL-KO ). AAV mCherry was used as control virus (WT). A pressor response to L-glutamate in the injection site served as confirmatory stereotactic target hit. RVL-targeted ablation of PRR resulted in lower BP responses to DOCA-salt in females (WT=115±3 vs KO=104±4 mmHg; p <0.05; n=8), but not males (n=5-8), only during the first 3 days of DOCA-salt treatment. However, at day 13 of DOCA-salt treatment, female PRR RVL-KO unexpectedly exhibited exaggerated increase in systolic BP (WT=149±3 vs KO=163±3 mmHg; p =0.004; n=8) and pulse pressure (WT=31±4 vs KO=45±4 mmHg; p =0.02; n=8) when compared to control. Next, mice were challenged with an intraperitoneal hypertonic saline injection equivalent to 10% of their body weight followed by 4 hours of urine collection. Urinary sodium excretion in female PRR RVL-KO was significantly lower when compared to WT ( p <0.05). These data indicate that the role of PRR in the RVL is sex-dependent and biphasic. That is, PRR contributes to the pressor response during the initial stage of DOCA-salt HT in females, presumably by facilitating the generation of angiotensin peptides in the RVL, while it plays a protective role by promoting renal sodium excretion and preventing elevation of systolic BP during the maintenance stage of DOCA-salt HT. This study suggests that distinct PRR expressing cell populations might elicit diverging physiological functions within the RVL.

Natriuretic response to renal interstitial hydrostatic pressure during angiotensin II blockade

1994 ◽  
Vol 266 (1) ◽  
pp. F117-F119 ◽  
Author(s):  
J. A. Haas ◽  
J. C. Lockhart ◽  
T. S. Larson ◽  
T. Henrikson ◽  
F. G. Knox
Keyword(s):  
Angiotensin Ii ◽  
Hydrostatic Pressure ◽  
Sodium Excretion ◽  
Renin Angiotensin System ◽  
Urinary Sodium Excretion ◽  
Treated Group ◽  
Sodium Reabsorption ◽  
Ang Ii ◽  
Angiotensin System ◽  
Before And After

Increases in renal interstitial hydrostatic pressure (RIHP) increase urinary sodium excretion (UNaV). Experimentally increasing RIHP by direct renal interstitial volume expansion (DRIVE) has been shown to decrease proximal tubule sodium reabsorption. The purpose of the present study was to investigate whether the renin-angiotensin system modulates the natriuretic response to DRIVE. Unilateral nephrectomy and implantation of two polyethylene matrices were performed 3 wk before the acute experiment. Fractional sodium excretion (FENa), RIHP, and glomerular filtration rate (GFR) were measured before and after DRIVE in control rats (n = 9) and in rats receiving the angiotensin II (ANG II) receptor antagonist, losartan potassium (10 mg/kg i.v.; n = 10). DRIVE was achieved by infusing 100 microliters of 2.5% albumin solution directly into the renal interstitium. GFR remained unchanged by DRIVE in both groups. In control animals, DRIVE significantly increased both RIHP (delta 3.8 +/- 0.5 mmHg) and FENa (delta 0.92 +/- 0.19%). In the losartan-treated group, RIHP (delta 2.8 +/- 0.4 mmHg) and FENa (delta 1.93 +/- 0.41%) also significantly increased. The natriuretic response to DRIVE was significantly enhanced during ANG II receptor blockade compared with control animals (delta UNaV/delta RIHP = 2.01 +/- 0.67 vs. 0.44 +/- 0.17 mu eq.min-1 x mmHg-1, respectively; P < 0.05). These results suggest that the blockade of angiotensin enhances the natriuretic response to increased RIHP during DRIVE.

scholarly journals Disruption of CXCR6 Ameliorates Kidney Inflammation and Fibrosis in Deoxycorticosterone Acetate/Salt Hypertension

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuanbo Wu ◽  
Changlong An ◽  
Xiaogao Jin ◽  
Zhaoyong Hu ◽  
Yanlin Wang
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Kidney Injury ◽  
Wild Type ◽  
Salt Treatment ◽  
Hypertensive Nephropathy ◽  
Deoxycorticosterone Acetate ◽  
Kidney Fibrosis ◽  
Salt Hypertension

AbstractCirculating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow–derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.

scholarly journals Exacerbated effects of prorenin on hypothalamic magnocellular neuronal activity and vasopressin plasma levels during salt-sensitive hypertension

2019 ◽  
Vol 317 (3) ◽  
pp. H496-H504
Author(s):  
Soledad Pitra ◽  
Caleb J. Worker ◽  
Yumei Feng ◽  
Javier E. Stern
Keyword(s):  
Plasma Levels ◽  
Renin Angiotensin System ◽  
Membrane Excitability ◽  
Hypertensive Rats ◽  
Deoxycorticosterone Acetate ◽  
Type K ◽  
Neurosecretory Neurons ◽  
Salt Hypertension ◽  
Underlying Mechanisms ◽  
Salt Sensitive Hypertension

Accumulating evidence supports that the brain renin-angiotensin system (RAS), including prorenin (PR) and its receptor (PRR), two newly discovered RAS players, contribute to sympathoexcitation in salt-sensitive hypertension. Still, whether PR also contributed to elevated circulating levels of neurohormones such as vasopressin (VP) during salt-sensitive hypertension, and if so, what are the precise underlying mechanisms, remains to be determined. To address these questions, we obtained patch-clamp recordings from hypothalamic magnocellular neurosecretory neurons (MNNs) that synthesize the neurohormones oxytocin and VP in acute hypothalamic slices obtained from sham and deoxycorticosterone acetate (DOCA)-salt-treated hypertensive rats. We found that focal application of PR markedly increased membrane excitability and firing responses in MNNs of DOCA-salt, compared with sham rats. This effect included a shorter latency to spike initiation and increased numbers of spikes in response to depolarizing stimuli and was mediated by a more robust inhibition of A-type K+ channels in DOCA-salt compared with sham rats. On the other hand, the afterhyperpolarizing potential mediated by the activation of Ca2+-dependent K+ channel was not affected by PR. mRNA expression of PRR, VP, and the Kv4.3 K+ channel subunit in the supraoptic nucleus of DOCA-salt hypertensive rats was increased compared with sham rats. Finally, we report a significant decrease of plasma VP levels in neuron-selective PRR knockdown mice treated with DOCA-salt, compared with wild-type DOCA-salt-treated mice. Together, these results support that activation of PRR contributes to increased excitability and firing discharge of MNNs and increased plasma levels of VP in DOCA-salt hypertension. NEW & NOTEWORTHY Our studies support that prorenin (PR) and its receptor (PRR) within the hypothalamus contribute to elevated plasma vasopressin levels in deoxycorticosterone acetate-salt hypertension, in part because of an exacerbated effect of PR on magnocellular neurosecretory neuron excitability; Moreover, our study implicates A-type K+ channels as key underlying molecular targets mediating these effects. Thus, PR/PRR stands as a novel therapeutic target for the treatment of neurohumoral activation in salt-sensitive hypertension.

P2X7 deficiency attenuates hypertension and renal injury in deoxycorticosterone acetate-salt hypertension

2012 ◽  
Vol 303 (8) ◽  
pp. F1207-F1215 ◽  
Author(s):  
Xu Ji ◽  
Yukiko Naito ◽  
Huachun Weng ◽  
Kosuke Endo ◽  
Xiao Ma ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Inflammatory Diseases ◽  
Receptor Expression ◽  
Salt Treatment ◽  
Deoxycorticosterone Acetate ◽  
Salt Diet ◽  
Salt Hypertension ◽  
Mrna And Protein Expression

The P2X7 receptor is a ligand-gated ion channel, and genetic variations in the P2X7 gene significantly affect blood pressure. P2X7 receptor expression is associated with renal injury and inflammatory diseases. Uninephrectomized wild-type (WT) and P2X7-deficient (P2X7 KO) mice were subcutaneously implanted with deoxycorticosterone acetate (DOCA) pellets and fed an 8% salt diet for 18 days. Their blood pressure was assessed by a telemetry system. The mice were placed in metabolic cages, and urine was collected for 24 h to assess renal function. After 18 days of DOCA-salt treatment, P2X7 mRNA and protein expression increased in WT mice. Blood pressure in P2X7 KO mice was less than that of WT mice (mean systolic blood pressure 133 ± 3 vs. 150 ± 2 mmHg). On day 18, urinary albumin excretion was lower in P2X7 KO mice than in WT mice (0.11 ± 0.07 vs. 0.28 ± 0.07 mg/day). Creatinine clearance was higher in P2X7 KO mice than in WT mice (551.53 ± 65.23 vs. 390.85 ± 32.81 μl·min−1·g renal weight−1). Moreover, renal interstitial fibrosis and infiltration of immune cells (macrophages, T cells, B cells, and leukocytes) were markedly attenuated in P2X7 KO mice compared with WT mice. The levels of IL-1β, released by macrophages, in P2X7 KO mice had decreased dramatically compared with that in WT mice. These results strongly suggest that the P2X7 receptor plays a key role in the development of hypertension and renal disease via increased inflammation, indicating its potential as a novel therapeutic target.

Increased renal atrial natriuretic peptide synthesis in rats with deoxycorticosterone acetate-salt treatment

1996 ◽  
Vol 271 (4) ◽  
pp. F779-F789 ◽  
Author(s):  
Y. J. Lee ◽  
S. J. Shin ◽  
M. S. Tan ◽  
T. J. Hsieh ◽  
J. H. Tsai
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Excretion Rate ◽  
Rat Kidney ◽  
Urinary Sodium Excretion ◽  
Treated Group ◽  
Urinary Sodium ◽  
Deoxycorticosterone Acetate ◽  
Low Salt

To investigate the role of renal synthesis of atrial natriuretic peptide (ANP) as a contributor to the water-sodium homeostasis, we studied the effects of electrolyte-water imbalance on renal ANP mRNA levels, plasma ANP concentrations, and urinary ANP excretion rates by using reverse transcription-polymerase chain reaction (PCR) and radioimmunoassay. Male Wistar rates divided into the following three groups: 1) the control group, 2) deoxycorticosterone acetate (DOCA)-salt-treated group, and 3) low-salt-treated group. The urinary sodium excretion rate and urine volume in the DOCA-salt rats were significantly elevated at 2 days and for the 10-day study. The urinary ANP excretion rate in DOCA-salt rats was significantly increased at 2 days after treatment and was well correlated to the urinary sodium excretion rate (r = 0.76, P < 0.01). Plasma ANP levels in the DOCA-salt rats were elevated on the day of death. In contrast, plasma renin activities were markedly suppressed in DOCA-salt rats and increased in low-salt rats. By immunohistochemical study, immunoreactive ANP materials were mainly localized in the proximal and distal cortical tubules of the kidney. With the PCR cloning and sequencing technique, ANP cDNA was cloned from the rat kidney, and the sequences were identical to that of ANP identified in the atria. By semiquantitative PCR technique, the expression of ANP mRNA in the ventricle and renal cortex tissues was significantly enhanced in the DOCA-salt rats. Our results confirm that the rat kidney is a site of ANP synthesis and indicate that renal ANP synthesis is enhanced in a volume-expansion state. We propose that renal synthesized natriuretic peptide participates in the intrarenal regulation of water-electrolyte homeostasis and may contribute to renal adaptation during the mineralocorticoid escape phenomenon.

Abstract P284: Neuron Specific (Pro)renin Receptor Knockout Reduces Sodium Appetite and Attenuates the Development of DOCA-salt Induced Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Fatima Trebak ◽  
Wencheng Li ◽  
Yumei Feng
Keyword(s):  
Fluid Intake ◽  
Sodium Intake ◽  
Renin Angiotensin System ◽  
Urinary Sodium Excretion ◽  
Free Access ◽  
Salt Treatment ◽  
Total Fluid Intake ◽  
Sodium Appetite ◽  
Induced Hypertension ◽  
Total Fluid

The (pro) renin receptor (PRR) is a key component of the renin-angiotensin system that is highly expressed in the brain. We previously showed that the neuronal PRR deletion attenuates deoxycorticosterone acetate (DOCA)-salt induced hypertension. However, the mechanism underlying remains unclear. To test our hypothesis that PRR is involved in the regulation of sodium appetite during DOCA-salt hypertension, we used a neuron-specific PRR knockout (PRRKO) mouse model generated using the Cre-LoxP system. The PRRKO and their wildtype controls (WT) were implanted with 50 mg DOCA pellet with free access to regular water and 0.9 % saline as the drinking solution. Blood pressure (BP) was monitored by telemetry system in conscious free moving mice. The fluid intake and urine output were monitored along 21 days of DOCA-Salt treatment. The BP is significantly lower in PRRKO compared with WT mice following 21 days of DOCA-salt treatment (112 ± 2 vs. 134 ± 7 mmHg, P= 0.0186). Interestingly, we found that saline intake (27.8 ± 1.8 vs. 15.9 ± 1.2 ml/day, P=0.0007) and total fluid intake (31.1 ± 1.9 vs. 21.1 ± 1.4 ml/day, P=0.003) were higher; while the regular water intake was lower (3.4 ± 0.6 vs. 5.2 ± 0.3 ml/day, P=0.03) in WT compared to PRRKO mice. PRR deletion in the neurons reduced sodium appetite presented as the ratio of saline intake over total fluid intake (0.75 ± 0.016 vs. 0.89 ± 0.019, P=0.0005), as well as total sodium intake (2.45 ± 0.19 vs. 4.28 ± 0.28 mmol/day, P=0.0007) compared with WT mice at the end of the protocol. In addition, the urinary sodium excretion was lower (13.3±1.17 vs. 20±1.17 mmol/day, P<0.0001), but not potassium excretion (0.64 ± 0.028 vs. 0.56 ± 0.05 mmol/day, P=0.1291) in PRRKO compared with WT mice; however, there is no difference in urine sodium and potassium concentrations. Furthermore, plasma vasopressin level (19.0 ± 2.7 vs. 33.6 ± 2.7 pg/ml, P=0.0037) is lower in the PRRKO compared with WT mice at the end of DOCA-salt treatment. In summary, PRR deletion in the neurons reduced sodium appetite, circulating vasopressin level, and attenuated the development of DOCA-salt induced hypertension. Taken together, the present findings suggest that PRR regulates the BP and plays a key role in salt-sensitive hypertension, at least in part, by modulating sodium appetite.

Sodium excretion following lesions of preoptic recess periventricular tissue in the rat

1983 ◽  
Vol 244 (6) ◽  
pp. R815-R822 ◽  
Author(s):  
S. L. Bealer
Keyword(s):  
Sodium Excretion ◽  
Pressor Response ◽  
Third Ventricle ◽  
Urinary Sodium Excretion ◽  
Sodium Balance ◽  
Electrolytic Ablation ◽  
Electrolytic Lesions ◽  
Sodium Metabolism ◽  
Experimental Treatments ◽  
Sodium Regulation

Electrolytic lesions of periventricular tissue surrounding the anteroventral third ventricle (AV3V) results in chronic hypernatremia and attenuates natriuresis following several experimental treatments. The present investigation was designed to determine if AV3V periventricular ablation results in acute postlesion alterations in sodium metabolism. Urinary sodium excretion was measured during 2-h periods for 6 h, and then daily for 7 days following either electrolytic ablation of AV3V periventricular tissue or control surgery. Similar measurements were carried out on unoperated control animals, and rats which had received either renal denervations or subcutaneous injections of deoxycorticosterone (DOC) prior to surgery. Lesions of the tissue surrounding the AV3V resulted in a natriuresis and polyuria that was not prevented by renal denervation or DOC treatment and was accompanied by a pressor response and decreased glomerular filtration rate. The initial natriuresis was followed by 2 days of sodium retention, which exceeded the amount necessary to restore sodium balance. These data demonstrate that ablation of AV3V periventricular tissue results in acute alterations in sodium metabolism, and support the hypothesis that tissue surrounding the AV3V contains neural elements critical for normal sodium regulation.

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