scholarly journals The macula densa prorenin receptor is essential in renin release and blood pressure control

2018 ◽  
Vol 315 (3) ◽  
pp. F521-F534 ◽  
Author(s):  
Anne D. M. Riquier-Brison ◽  
Arnold Sipos ◽  
Ágnes Prókai ◽  
Sarah L. Vargas ◽  
lldikó Toma ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Macula Densa ◽  
Conditional Knockout ◽  
Renin Release ◽  
Sensory Cells ◽  
Anatomical Site ◽  
Functional Link ◽  
Prorenin Receptor

The prorenin receptor (PRR) was originally proposed to be a member of the renin-angiotensin system (RAS); however, recent work questioned their association. The present paper describes a functional link between the PRR and RAS in the renal juxtaglomerular apparatus (JGA), a classic anatomical site of the RAS. PRR expression was found in the sensory cells of the JGA, the macula densa (MD), and immunohistochemistry-localized PRR to the MD basolateral cell membrane in mouse, rat, and human kidneys. MD cell PRR activation led to MAP kinase ERK1/2 signaling and stimulation of PGE2 release, the classic pathway of MD-mediated renin release. Exogenous renin or prorenin added to the in vitro microperfused JGA-induced acute renin release, which was inhibited by removing the MD or by the administration of a PRR decoy peptide. To test the function of MD PRR in vivo, we established a new mouse model with inducible conditional knockout (cKO) of the PRR in MD cells based on neural nitric oxide synthase-driven Cre-lox recombination. Deletion of the MD PRR significantly reduced blood pressure and plasma renin. Challenging the RAS by low-salt diet + captopril treatment caused further significant reductions in blood pressure, renal renin, cyclooxygenase-2, and microsomal PGE synthase expression in cKO vs. wild-type mice. These results suggest that the MD PRR is essential in a novel JGA short-loop feedback mechanism, which is integrated within the classic MD mechanism to control renin synthesis and release and to maintain blood pressure.

Macula Densa NOS1β Modulates Renal Hemodynamics and Blood Pressure During Pregnancy: Role in Gestational Hypertension

2021 ◽  
pp. ASN.2020070969
Author(s):  
Jin Wei ◽  
Jie Zhang ◽  
Shan Jiang ◽  
Lan Xu ◽  
Larry Qu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Gestational Hypertension ◽  
Critical Role ◽  
Normal Pregnancy ◽  
Renal Hemodynamics ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Renal Tubules

Background: Regulation of renal hemodynamics and blood pressure (BP) via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing glomerular filtration rate (GFR) to increase and BP to decrease. Methods: We employed sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radio-telemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice. Results: Macula densa NOS1β was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1β, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1β expression increased in normotensive pregnancies but decreased in spontaneous gestational hypertensive pregnancies. Conclusions: Macula densa NOS1β plays a critical role in control of renal hemodynamics and BP during pregnancy.

Cardiovascular Effects of Micromeria graeca (L.) Benth. ex Rchb in Normotensive and Hypertensive Rats

2020 ◽  
Vol 20 (8) ◽  
pp. 1253-1261
Author(s):  
Mourad Akdad ◽  
Mohamed Eddouks
Keyword(s):  
Blood Pressure ◽  
Cardiovascular System ◽  
Arterial Blood Pressure ◽  
Antihypertensive Activity ◽  
Computer Assisted ◽  
Hypertensive Rats ◽  
Vasorelaxant Effect ◽  
Arterial Blood

Aims: The present study was performed in order to analyze the antihypertensive activity of Micromeria graeca (L.) Benth. ex Rchb. Background: Micromeria graeca (L.) Benth. ex Rchb is an aromatic and medicinal plant belonging to the Lamiaceae family. This herb is used to treat various pathologies such as cardiovascular disorders. Meanwhile, its pharmacological effects on the cardiovascular system have not been studied. Objective: The present study aimed to evaluate the effect of aqueous extract of aerial parts of Micromeria graeca (AEMG) on the cardiovascular system in normotensive and hypertensive rats. Methods: In this study, the cardiovascular effect of AEMG was evaluated using in vivo and in vitro investigations. In order to assess the acute effect of AEMG on the cardiovascular system, anesthetized L-NAME-hypertensive and normotensive rats received AEMG (100 mg/kg) orally and arterial blood pressure parameters were monitored during six hours. In the sub-chronic study, rats were orally treated for one week, followed by blood pressure assessment during one week of treatment. Blood pressure was measured using a tail-cuff and a computer-assisted monitoring device. In the second experiment, isolated rat aortic ring pre-contracted with Epinephrine (EP) or KCl was used to assess the vasorelaxant effect of AEMG. Results: Oral administration of AEMG (100 mg/kg) provoked a decrease of arterial blood pressure parameters in hypertensive rats. In addition, AEMG induced a vasorelaxant effect in thoracic aortic rings pre-contracted with EP (10 μM) or KCl (80 mM). This effect was attenuated in the presence of propranolol and methylene blue. While in the presence of glibenclamide, L-NAME, nifedipine or Indomethacin, the vasorelaxant effect was not affected. Conclusion: This study showed that Micromeria graeca possesses a potent antihypertensive effect and relaxes the vascular smooth muscle through β-adrenergic and cGMP pathways.

Vasorelaxant and Antihypertensive Effects of Mentha pulegium L. in Rats: An in vitro and in vivo Approach

2020 ◽  
Vol 20 ◽  
Author(s):  
Mohammed Ajebli ◽  
Mohamed Eddouks
Keyword(s):  
Blood Pressure ◽  
Acute Experiment ◽  
Antihypertensive Activity ◽  
Mentha Pulegium ◽  
In Vitro Experiment ◽  
Arterial Blood ◽  
Dose Dependent ◽  
Ca2 Channels

Aims and objective: The aim of the study was to investigate the effect of aqueous aerial part extract of Mentha pulegium L. (Pennyrile) (MPAE) on arterial pressure parameters in rats. Background: Mentha pulegium is a medicinal plant used to treat hypertension in Morocco. Material and methods: In the current study, MPAE was prepared and its antihypertensive activity was pharmacologically investigated. L-NAME-hypertensive and normotensive rats have received orally MPAE (180 and 300 mg/kg) during six hours for the acute experiment and during seven days for the sub-chronic treatment. Thereafter, systolic, diastolic, mean arterial blood pressure and heart rate were evaluated. While, in the in vitro experiment, isolated denuded and intact thoracic aortic rings were suspended in a tissue bath system and the tension changes were recorded. Results: A fall in blood pressure was observed in L-NAME-induced hypertensive treated with MPAE. The extract also produced a dose-dependent relaxation of aorta pre-contracted with NE and KCl. The study showed that the vasorelaxant ability of MPAE seems to be exerted through the blockage of extracellular Ca2+ entry. Conclusion: The results demonstrate that the extract of pennyrile exhibits antihypertensive activity. In addition, the effect may be, at least in part, due to dilation of blood vessels via blockage of Ca2+ channels.

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

scholarly journals Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 210-223 ◽  
Author(s):  
Eun Ji Gang ◽  
Hye Na Kim ◽  
Yao-Te Hsieh ◽  
Yongsheng Ruan ◽  
Heather A. Ogana ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

scholarly journals Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Lifeng Feng ◽  
Miaoqin Chen ◽  
Yiling Li ◽  
Muchun Li ◽  
Shiman Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cell Growth ◽  
Knockout Mice ◽  
Liver Tumors ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Conditional Knockout

Abstractp62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

Abstract 066: The Undescribed Protein Caskin2 Is a Novel Regulator of eNOS Phosphorylation and Systemic Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Sarah B Mueller ◽  
Susan B Gurley ◽  
Christopher D Kontos
Keyword(s):  
Blood Pressure ◽  
Molecular Mechanisms ◽  
Systemic Blood Pressure ◽  
Regulatory Subunit ◽  
Systemic Blood ◽  
Homologous Expression ◽  
Ongoing Work ◽  
Inducing Factors

Disruptions in the function of the quiescent endothelial cells (ECs) that line mature vessels can both result in and contribute to the progression of numerous cardiovascular diseases including hypertension, atherosclerosis, and disorders of vascular permeability. Despite recent attention, the signaling pathways that are active in quiescent ECs remain poorly characterized relative to those that regulate EC activation. In an effort to provide mechanistic insight into these pathways, we have characterized the previously undescribed protein Caskin2, which we hypothesize is a novel regulator of EC quiescence. Caskin2 is expressed in ECs throughout the vasculature, including the aorta, coronary arteries, and renal glomeruli. In vitro, Caskin2 promotes a quiescent EC phenotype characterized by decreased proliferation and increased resistance to apoptosis-inducing factors. Caskin2 knockout mice are viable and fertile. However, preliminary radiotelemetry measurements indicate that Caskin2 knockout (KO) mice have mildly elevated systemic blood pressure (BP). Compared to wild type (WT) littermates (n=8), Caskin2 KO mice (n=7) had increased mean arterial pressure (119+/-1 vs. 113+/-1, p=0.012), systolic BP (138+/-2 vs. 132+/-2, p=0.023), and diastolic BP (99+/-1 vs. 93+/-1, p=0.014) at baseline. To explore the molecular mechanisms of Caskin2’s effects, we used mass spectrometry to identify interacting proteins. Among the 67 proteins identified were the Ser/Thr phosphatase protein phosphatase 1 (PP1) and eNOS. Using standard in vitro biochemical techniques, we demonstrated that Caskin2 acts as a PP1 regulatory subunit. Interestingly, homologous expression of Caskin2 in vitro resulted in a marked increase in phosphorylation of eNOS on S1177, which is known to promote eNOS activity, and a decrease in phosphorylation on T495, which is associated with eNOS inhibition. Finally, PP1 has been shown to dephosphorylate eNOS T495 in vitro, suggesting a molecular mechanism for our in vivo findings. Ongoing work aims to determine if the interaction of Caskin2 and PP1 is required for the Caskin2-induced increase in activating phosphorylation of eNOS and to characterize the physiological mechanisms responsible for Caskin2’s effects on BP in more detail.

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daniel J Fehrenbach ◽  
Meena S Madhur
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Repeated Measures ◽  
Flow Cytometric Analysis ◽  
Coiled Coil ◽  
Ang Ii ◽  
Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

scholarly journals 5-HT causes splanchnic venodilation

2017 ◽  
Vol 313 (3) ◽  
pp. H676-H686 ◽  
Author(s):  
Bridget M. Seitz ◽  
Hakan S. Orer ◽  
Teresa Krieger-Burke ◽  
Emma S. Darios ◽  
Janice M. Thompson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Inferior Vena Cava ◽  
Portal Vein ◽  
Superior Mesenteric Vein ◽  
Inferior Vena ◽  
Vena Cava ◽  
Receptor Protein ◽  
Mesenteric Vein

Serotonin [5-hydroxytryptamine (5-HT)] causes relaxation of the isolated superior mesenteric vein, a splanchnic blood vessel, through activation of the 5-HT7 receptor. As part of studies designed to identify the mechanism(s) through which chronic (≥24 h) infusion of 5-HT lowers blood pressure, we tested the hypothesis that 5-HT causes in vitro and in vivo splanchnic venodilation that is 5-HT7 receptor dependent. In tissue baths for measurement of isometric contraction, the portal vein and abdominal inferior vena cava relaxed to 5-HT and the 5-HT1/7 receptor agonist 5-carboxamidotryptamine; relaxation was abolished by the 5-HT7 receptor antagonist SB-269970. Western blot analyses showed that the abdominal inferior vena cava and portal vein express 5-HT7 receptor protein. In contrast, the thoracic vena cava, outside the splanchnic circulation, did not relax to serotonergic agonists and exhibited minimal expression of the 5-HT7 receptor. Male Sprague-Dawley rats with chronically implanted radiotelemetry transmitters underwent repeated ultrasound imaging of abdominal vessels. After baseline imaging, minipumps containing vehicle (saline) or 5-HT (25 μg·kg−1·min−1) were implanted. Twenty-four hours later, venous diameters were increased in rats with 5-HT-infusion (percent increase from baseline: superior mesenteric vein, 17.5 ± 1.9; portal vein, 17.7 ± 1.8; and abdominal inferior vena cava, 46.9 ± 8.0) while arterial pressure was decreased (~13 mmHg). Measures returned to baseline after infusion termination. In a separate group of animals, treatment with SB-269970 (3 mg/kg iv) prevented the splanchnic venodilation and fall in blood pressure during 24 h of 5-HT infusion. Thus, 5-HT causes 5-HT7 receptor-dependent splanchnic venous dilation associated with a fall in blood pressure. NEW & NOTEWORTHY This research is noteworthy because it combines and links, through the 5-HT7 receptor, an in vitro observation (venorelaxation) with in vivo events (venodilation and fall in blood pressure). This supports the idea that splanchnic venodilation plays a role in blood pressure regulation.

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