Abstract P100: (Pro)renin Receptor (PRR) Mediates Renal Inflammation in Renovascular Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Syed Siraj Ahmed Quadri ◽  
Caixia Li ◽  
Silas Culver ◽  
Helmy M Siragy
Keyword(s):  
Blood Pressure ◽  
Renovascular Hypertension ◽  
Blood Pressure Reduction ◽  
Left Renal Artery ◽  
Sprague Dawley ◽  
Renal Inflammation ◽  
Arterial Blood ◽  
Tnf Α ◽  
Protein Expressions ◽  
Cox 2

We hypothesized that PRR plays a role in renal inflammation in 2-kidney, 1-clip (2K1C) hypertension rat model. Male Sprague-Dawley rats were fed normal sodium diet. BP was obtained before and 28 days after left renal artery clipping. Renal expressions of PRR, TNF-α and COX-2 were assessed in sham and 2K1C rats with or without left renal interstitial administration of scramble shRNA or PRR shRNA. At baseline there were no significant differences in BP between different animal groups. Compared to sham, mean arterial blood pressure significantly increased in 2K1C (2K1C 131.8 ± 3.09 mmHg, vs. sham 108 ± 1.9 mmHg, P<0.0.05) at day 28 and was not influenced by scramble shRNA or PRR shRNA treatment. Compared to sham and contra lateral (non-clipped) kidney, there were increases in mRNA and protein expressions of PRR (90% and 45%, P<0.01), TNF-α (72% and 50%, P<0.05), COX-2 (72% and 39%, P<0.05) in the clipped kidney. These expressions were not influenced by scramble shRNA treatment. Compared to 2K1C (no treatment) and scramble shRNA, PRR shRNA treatment in the clipped kidney caused significant reductions in mRNA and protein expressions of PRR (60% and 54%, P<0.01, shown in figure below), TNF-α (54% and 51%, P<0.05), COX-2 (51% and 53%, P<0.05). We conclude that PRR mediates renal inflammation in renovascular hypertension independent of blood pressure reduction.

Abstract 71: Novel Bach1 Modulators Increase HMOX1 and Suppress Hypertension in the Goldblatt Model of Renovascular Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Matthew Kostura ◽  
Otis Attucks ◽  
Jareer Kassis ◽  
Suparna Gupta ◽  
Samuel Victory ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Enzyme Activity ◽  
Renovascular Hypertension ◽  
Transcriptional Repressor ◽  
Plasma Aldosterone ◽  
Lung Fibroblasts ◽  
Left Renal Artery ◽  
Dependent Manner ◽  
Sprague Dawley

We report for the first time a novel class of compounds that specifically modulate the Bach1 transcriptional repressor pathway. In cellula, the compounds selectively inhibit the activity of the transcriptional repressor Bach1 resulting in transcription of a network of antioxidant and cytoprotective genes including HMOX1. HPP-1971, a member of this class, is a potent and selective Bach1 inhibitor that induces HMOX1 > 40-fold with a potency of 408 nM in human lung fibroblasts. To assess activity in vivo, we tested HPP-1971 in the Goldblatt model of renovascular hypertension. Sprague Dawley rats were implanted with in dwelling pressure telemeter probes and subsequently underwent sham surgery or placement of a 0.25 mm silver clip around the left renal artery. HPP-1971 treatment, dosed orally at 1,3,10 and 30 mpk, commenced three days following clip surgery, and continued for 18 days. At study completion, blood pressure, clipped kidney weight, renal HMOX1 enzyme activity and plasma aldosterone levels were measured (see Table). HPP-1971 attenuated both kidney atrophy and the increase in blood pressure in a dose dependent manner with significant differences seen at 3, 10 and 30 mpk (p<.0001). HMOX1 enzyme activity in the clipped kidney increased with treatment, reaching a maximum of 5.7 ± 0.9 nM/hr/mg at 30 mpk relative to sham operated animals (p<.0001). Plasma aldosterone levels increased in 2K1C animals compared to sham controls but were reduced by HPP-1971 treatment. These findings define a novel role for Bach1 suppressors in counteracting the influence of the RAAS system on hypertension and kidney atrophy in the 2K1C model of renovascular hypertension.

Abstract 413: Renal Cyclooxygenase-2 Expression And Hemodynamic Role During Angiotensin II-dependent Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Alexis A Gonzalez ◽  
Torrance Green ◽  
Camille R Bourgeois ◽  
Christina Luffman ◽  
Minolfa C Prieto ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Late Phase ◽  
Renal Hemodynamics ◽  
Cyclooxygenase 2 ◽  
Kidney Cortex ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Cox 2

Intrarenal cyclooxygenase-2 (COX-2) activity is increased during activation of the renin-angiotensin-system (RAS) increasing synthesis of prostaglandin E2 (PGE2) and buffering the vasoconstrictor and antinatriuretic effects of angiotensin II (AngII). While AngII upregulates intrarenal COX-2 expression, it remains unclear if this occurs in a time-dependent manner, thereby impacting renal hemodynamics differently during the early and late phases of the development of high blood pressure in AngII-induced hypertension. Male Sprague-Dawley rats were infused with AngII (0.4 μg/min/kg). Systolic blood pressure (SBP), COX-2 expression and PGE2 tissue content and urinary excretion were evaluated at day 3, 7 and 14 of the AngII infusions. In acute studies we evaluated the effects of COX-2 inhibition at day 5-7 and day 14 on renal hemodynamic parameters. Chronic AngII infusions increased SBP from day 7 through 14: 162 ± 5 mmHg; and 198 ± 15 mmHg versus controls: 114 ± 10 mmHg; P<0.05. COX-2 mRNA and protein levels were high in kidney cortex only at day 3 (mRNA: 241 ± 56%, protein: 160 ± 21%, P<0.05 versus controls). Medullary COX-2 mRNA and protein were increased on days 3 (mRNA: 176 ± 20%, protein: 185 ± 32%, P<0.05 versus controls), 7 (mRNA: 189 ± 23%, protein: 158 ± 15%, P<0.05 versus controls) and 14 (mRNA: 148 ± 15%, protein: 135 ± 13%, P<0.05 versus controls). Urinary and medullary PGE2 increased by day 3 and remained elevated during days 7 and 14. COX-2 inhibition decreased GFR and renal blood flow in AngII infused rats during both the early and late phases. Interestingly, COX-2 inhibition decreased mean arterial blood pressure at day 14 of AngII-infusion (COX-2 inhibition: 124 ± 9 versus 140 ± 7 mmHg, P<0.05) but not during the early normotensive phase (COX-2 inhibition: 110 ± 4 versus 115± 4 mmHg, P=NS). These results indicate that enhanced medullary COX-2 expression and PGE2 production during both the early and late phases attenuates the effects of AngII on renal hemodynamics. However COX-2 inhibition at day 14 reduced blood pressure, suggesting that a vasoconstrictor COX-2 metabolite contributes to the hypertension during the late phase.

Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension

2011 ◽  
Vol 89 (2) ◽  
pp. 103-107 ◽  
Author(s):  
Vivian Boshra ◽  
Gehan Abdel Hamid El Wakeel ◽  
Manar A Nader
Keyword(s):  
Blood Pressure ◽  
Renovascular Hypertension ◽  
Aortic Coarctation ◽  
Oral Treatment ◽  
Antihypertensive Agents ◽  
Plasma Renin ◽  
Prostaglandin E ◽  
Sprague Dawley ◽  
Hypertensive Patients ◽  
Arterial Blood

Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30 mg/kg), celecoxib (3 mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2(PGE2) in male Sprague–Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure.

scholarly journals Increased superoxide levels in ganglia and sympathoexcitation are involved in sarafotoxin 6c-induced hypertension

2008 ◽  
Vol 295 (5) ◽  
pp. R1546-R1554 ◽  
Author(s):  
Melissa Li ◽  
Xiaoling Dai ◽  
Stephanie Watts ◽  
David Kreulen ◽  
Gregory Fink
Keyword(s):  
Blood Pressure ◽  
Sympathetic Innervation ◽  
Sympathetic Ganglia ◽  
Plasma Norepinephrine ◽  
Sprague Dawley ◽  
Surgical Ablation ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Hypertension Development

Endothelin (ET) type B receptors (ETBR) are expressed in multiple tissues and perform different functions depending on their location. ETBR mediate endothelium-dependent vasodilation, clearance of circulating ET, and diuretic effects; all of these should produce a fall in arterial blood pressure. However, we recently showed that chronic activation of ETBR in rats with the selective agonist sarafotoxin 6c (S6c) causes sustained hypertension. We have proposed that one mechanism of this effect is constriction of capacitance vessels. The current study was performed to determine whether S6c hypertension is caused by increased generation of reactive oxygen species (ROS) and/or activation of the sympathetic nervous system. The model used was continuous 5-day infusion of S6c into male Sprague-Dawley rats. No changes in superoxide anion levels in arteries and veins were found in hypertensive S6c-treated rats. However, superoxide levels were increased in sympathetic ganglia from S6c-treated rats. In addition, superoxide levels in ganglia increased progressively the longer the animals received S6c. Treatment with the antioxidant tempol impaired S6c-induced hypertension and decreased superoxide levels in ganglia. Acute ganglion blockade lowered blood pressure more in S6c-treated rats than in vehicle-treated rats. Although plasma norepinephrine levels were not increased in S6c hypertension, surgical ablation of the celiac ganglion plexus, which provides most of the sympathetic innervation to the splanchnic organs, significantly attenuated hypertension development. The results suggest that S6c-induced hypertension is partially mediated by sympathoexcitation to the splanchnic organs driven by increased oxidative stress in prevertebral sympathetic ganglia.

Abstract 119: Influence of Anesthetics on the Hemodynamic Response in a Rat Model of Hemorrhagic Shock

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Claudius Balzer ◽  
Franz J Baudenbacher ◽  
Susan S Eagle ◽  
Michele M Salzman ◽  
William J Cleveland ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Hemorrhagic Shock ◽  
Rat Model ◽  
Cardiovascular Response ◽  
Femoral Vein ◽  
Blood Pressure Measurement ◽  
Experimental Models ◽  
Sprague Dawley ◽  
Compensatory Mechanisms ◽  
Arterial Blood

Introduction: Experimental models of hemorrhagic shock (HS) in rats are important to test new treatments that may improve outcomes in humans, and general anesthesia is required during these experiments. The volatile anesthetic Isoflurane is known for its beneficial effects in rat HS models. Focusing on cardiovascular compensatory mechanisms, we wanted to evaluate Isoflurane versus the injectable anesthetic Pentobarbital in our rat model of mild HS (class 2). We hypothesize that Isoflurane during development of HS improves hemodynamics compared to Pentobarbital. Methods: Twelve Sprague-Dawley rats were initially anesthetized with an intraperitoneal (IP) injection of Pentobarbital (45 mg/kg) and intubated (1 L/min, FiO 2 0.25); heart rate (HR) was monitored by subcutaneous ECG needles. Femoral artery and vein were cannulated for continuous blood pressure measurement and delivery of fluids, respectively. In one group (n=7), anesthesia was continued with repeated IP injections of Pentobarbital (dose mg/kg), the other group (n=5) received continuous Isoflurane (1%). After 30 min of stabilization and administration of Heparin (100 IU/kg), HS was induced by removal of 1 ml of blood over 1 min via the femoral vein, repeated every 3 min until a volume of 5 ml of blood was removed. Mean arterial blood pressure (MAP) and HR were recorded and analyzed in LabChart. Results: During baseline, rats showed no significant differences in HR and MAP between both groups. After 5 ml of hemorrhage, both groups showed significant changes compared to baseline, with significantly higher MAP and HR in rats given only Pentobarbital. Conclusions: In our rat model of HS, Isoflurane dampens the physiologic response to compensate for mild hemorrhage. The cardiovascular response of rats in the Isoflurane group was a decrease of HR and MAP to every ml of hemorrhage, while rats given only Pentobarbital were able to maintain their MAP by raising their HR until decompensation.

Abstract P489: Effect of Continuous Intake of Hesperidin on Blood Pressure in 2-kidney, 1-clip Renovasucular Hypertensive Rats

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ayuna Yamaoka ◽  
Yukiko Segawa ◽  
Saki Maruyama ◽  
Natsumi Saito ◽  
Hiroko Hashimoto ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mrna Expression ◽  
Control Diet ◽  
Left Renal Artery ◽  
Sham Operation ◽  
Hypertensive Rats ◽  
Fruit Peel ◽  
Arterial Blood ◽  
Significant Difference ◽  
Enos Mrna

Objective: Hesperidin (HES) is a flavonoid which is contained in citrus fruit peel. It has physiological effects on blood vessels such as strengthening capillary vessels. Thus, it is known to be one of the effective ingredients of herbal medicine. Some studies have shown that the intake of HES decreases blood pressure (BP) in spontaneously hypertensive rats. The antihypertensive effect of HES is suggested to be due to vasodilation by nitric oxide (NO). However, its mechanism has not been clarified in detail. In this study, we observed whether HES intake decreases BP in 2-kidney, 1-clip renovasucular hypertensive rats (2K1C) and evaluated endothelial NO synthase (eNOS) mRNA to investigate its role in the mechanism. Methods: Male Sprague-Dawley rats (6 weeks old) were treated with sham operation (SHAM) or clipping the left renal artery (2K1C). After surgery, the rats started receiving continuously a control diet (C) or a diet containing 0.1% (w/w) HES for 6 weeks. The systolic BP (SBP) was measured by a tail-cuff method every week. At the end of the protocol, mean arterial blood pressure (MAP) was measured in each rat under anesthesia. Then, the aortas were removed for extracting mRNA. eNOS mRNA expression was evaluated using real-time RT-PCR. Results: At the end of the protocol, SBP in 2K1C-C was significantly higher than in SHAM-C (170±6 vs 117±6 mmHg, p <0.001). On the other hand, 2K1C-HES was lower in SBP (141±4 mmHg) than 2K1C-C ( p <0.01). There were no significant differences between SHAM-HES (122±7 mmHg) and SHAM-C. MAP at the end of the protocol were similar to in SBP. ANOVA revealed mRNA expression of eNOS was significantly higher in 2K1C than in SHAM ( p <0.05), and showed no significant difference between C and HES, nor a significant interaction. Conclusion: Continuous intake of HES may suppress BP increase in 2K1C. The role of eNOS mRNA expression may not be involved in the mechanism.

Abstract 620: Chronic Allium Bakeri Intake Alleviated Hypertension and Aortic Media Thickness in 2-Kidney, 1-Clip Rats.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Saori Kitamura ◽  
Hiroko Hashimoto ◽  
Yukiko Segawa ◽  
Nobutaka Kurihara
Keyword(s):  
Renovascular Hypertension ◽  
Transient Receptor Potential ◽  
Control Diet ◽  
Receptor Potential ◽  
Left Renal Artery ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Media Thickness ◽  
Freeze Dried ◽  
Aortic Media

Objective: Allium bakeri (AB) known as “rakkyo” and Allium sativum known as “garlic” contain alliin. Alliin easily turns into allicin, which is reported to decrease blood pressure (BP) through activating the excitatory ion channel transient receptor potential ankyrin-1. Thus, it is suggested that these vegetable decrease BP. Actually, garlic is reported to decrease BP and aortic media thickness in hypertensive animal models. However, it is practically difficult that garlic shows the effects, because it can hardly be eaten without heating and allicin is thermolabile. On the other hand, AB is usually eaten without heating. Therefore, in this study, we tested whether AB intake alleviates hypertension and aortic media thickness in hypertensive rats. Method: We used 2-kidney, 1-clip (2K1C) renovascular hypertension model. Male Sprague-Dawley rats (6 wo) were treated with sham operation (SHAM) or clipping the left renal artery (2K1C). After surgery, SHAM and 2K1C rats were respectively divided into 2 groups, which received a control diet (CONT) or a diet containing 1.0 % (w/w) freeze-dried AB powder for 7 weeks (AB). The systolic BP (SBP) was measured by a tail-cuff method every week. At the end of the protocol, mean arterial BP (MAP) was measured in each rat under anesthesia. Then, thoracic aorta was removed and the section of aorta was stained with hematoxylin and eosin. Results: From the 2nd week after surgery until the end of the protocol, SBP in 2K1C-CONT went up significantly compared with SHAM-CONT (174 ± 7 vs 120 ± 5 mmHg, at the end of the protocol, P < 0.01). However, SBP in 2K1C-AB did not go up through the protocol (127 ± 7 mmHg, P < 0.01 with 2K1C-CONT, at the end). In addition, the AB diet showed no significant effects on SBP in SHAM. These observations in SBP were similar to in MAP at the end of the protocol. The aortic media thickening was observed in 2K1C-CONT compared with SHAM-CONT. In 2K1C-AB, the thickness was significantly decreased compared with 2K1C-CONT, and was not significantly different from that in SHAM-AB. There were not significant differences between SHAM-CONT and SHAM-AB. Conclusion: Chronic intake of Allium bakeri, which can be eaten without heating, alleviated hypertension and aortic media thickness in rats with renovascular hypertension.

Exercise training and its effects with renal hypertensive rats

1985 ◽  
Vol 59 (5) ◽  
pp. 1410-1415 ◽  
Author(s):  
K. D. Marcus ◽  
C. M. Tipton
Keyword(s):  
Blood Pressure ◽  
Exercise Training ◽  
Capillary Density ◽  
Heart Weight ◽  
Sprague Dawley ◽  
Vo2 Max ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Resting Blood Pressure ◽  
Renal Hypertensive Rats

The influence of endurance training on functional capacity [maximal O2 consumption (VO2 max)], caudal arterial blood pressure, and myocardial capillary density were investigated in normotensive rats and rats made hypertensive using the two-kidney one-clip approach (Goldblatt's hypertension). Male Sprague-Dawley rats were assigned to sham (N: 120–140 mmHg), moderately hypertensive (MH = 0.30-mm clips, 150–170 mmHg), or severely hypertensive (SH = 0.25-mm clips, 190–230 mmHg) groups. Rats designated to be runners (T) were exercised on a motor-driven treadmill equal to 50–70% of their VO2 max values for 8–12 wk. Compared with their nontrained (NT) controls, training was associated with significantly higher VO2 max values (12–15%) and muscle cytochrome-c oxidase activities (33–78%). Resting systolic blood pressure was not significantly changed in the N-and MH-T subgroups; however, it was 20–30 mmHg higher in the SH-T subgroup. Mean absolute heart weight for only the N-T group was significantly heavier than their NT controls. However, the mean predicted heart weights (heart wt = 0.639 X body wt of N-NT + 0.001 g) of the two SH groups were significantly higher than expected. The SH-T group had a lower (11%) subepicardial capillary density mean than its NT control and significantly fewer capillaries in the subendocardial region than the other five subgroups. It was concluded that moderate exercise training appeared to be detrimental to rats with severe hypertension because it increased resting blood pressure and decreased myocardial capillary density, even though it improved their functioning capacity.

Increased renal α-ENaC and NCC abundance and elevated blood pressure are independent of hyperaldosteronism in vasopressin escape

2006 ◽  
Vol 291 (1) ◽  
pp. F49-F57 ◽  
Author(s):  
Swasti Tiwari ◽  
Randall K. Packer ◽  
Xinqun Hu ◽  
Yoshihisa Sugimura ◽  
Joseph G. Verbalis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Sprague Dawley ◽  
Α Subunit ◽  
Water Load ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Solid Diet ◽  
Epithelial Sodium Channel Enac

Previously, we demonstrated that rats undergoing vasopressin escape had increased mean arterial blood pressure (MAP), plasma and urine aldosterone, and increased renal protein abundance of the α-subunit of the epithelial sodium channel (ENaC), the thiazide-sensitive Na-Cl cotransporter (NCC), and the 70-kDa band of γ-ENaC (Song J, Hu X, Khan O, Tian Y, Verbalis JG, and Ecelbarger CA. Am J Physiol Renal Physiol 287: F1076–F1083, 2004; Ecelbarger CA, Knepper MA, and Verbalis JG. J Am Soc Nephrol 12: 207–217, 2001). Here, we determine whether changes in these renal proteins and MAP require elevated aldosterone levels. We performed adrenalectomies (ADX) or sham surgeries on male Sprague-Dawley rats. Corticosterone and aldosterone were replaced to clamp these hormone levels. MAP was monitored by radiotelemetry. Rats were infused with 1-deamino-[8-d-arginine]-vasopressin (dDAVP) via osmotic minipumps (5 ng/h). At day 3 of dDAVP infusion, seven rats in each group were offered a liquid diet [water load (WL)] or continued on a solid diet (SD). Plasma aldosterone and corticosterone and urine aldosterone were increased by WL in sham rats. ADX-WL rats escaped, as assessed by early natriuresis followed by diuresis; however, urine volume and natriuresis were somewhat blunted. WL did not reduce the abundance or activity of 11-β-hydroxsteroid dehydrogenase type 2. Furthermore, the previously observed increase in renal aldosterone-sensitive proteins and escape-associated increased MAP persisted in clamped rats. The densitometry of immunoblots for NCC, α- and γ-70 kDa ENaC, respectively, were (% sham-SD): sham-WL, 159, 278, 233; ADX-SD, 69, 212, 171; ADX-WL, 116, 302, 161. However, clamping corticosteroids blunted the rise at least for NCC and γ-ENaC (70 kDa). Overall, the increase in aldosterone observed in vasopressin escape is not necessary for the increased expression of NCC, α- or γ-ENaC or increased MAP associated with “escape.”

Abstract MP57: Chronic Inhibition Of Brain Rhomboid-like Protein 2 (irhom2) Activity Decreases Arterial Blood Pressure In Salt-sensitive Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Mazher Mohammed ◽  
Mona Elgazzaz ◽  
Clara Berdasco ◽  
Eric D Lazartigues
Keyword(s):  
Blood Pressure ◽  
Neutralizing Antibody ◽  
Experimental Models ◽  
Arterial Blood ◽  
Artificial Cerebrospinal Fluid ◽  
Tnf Α ◽  
Significant Attenuation ◽  
Factor Α ◽  
Salt Sensitive Hypertension ◽  
The Brain

We previously reported that ADAM17 (aka tumor necrosis factor-α convertase) is critical for the development of hypertension in experimental models and patients. Recent studies highlighted that ADAM17’s formation of TNF-α relies on prior maturation of this sheddase, controlled by the rhomboid-like protein 2 (iRhom2) specifically in microglia. Genetic deletion of iRhom2 in mice shows significant attenuation of TNF-α and ADAM17 activity in a tissue specific manner. Here, we hypothesized that silencing iRhom2 activity specifically in the brain would decrease blood pressure (BP) in the DOCA-salt model of hypertension, in mice. Uninephrectomized mice were implanted subcutaneously (sc) with DOCA-pellets (50 mg) and provided with 1% saline in drinking water. In addition, mice were chronically implanted with an icv cannula connected to a sc osmotic minipump for delivery of: (1) iRhom2-siRNA (9.6 μg/kg/day), (2) scrambled siRNA (SCR 0.2 μg/kg/day), (3) ADAM17 antibody (ADAM17-Ab; 23.8 μg/kg/day) or (4) artificial cerebrospinal fluid (aCSF) for 2 weeks while BP was recorded by telemetry. DOCA-salt treatment led to a significant increase in BP in the control groups (SCR: 156 ±3 mmHg and aCSF: 161 ±1 mmHg; n=3/group; p<0.001) compared to baseline values (122 ±2 mmHg; n=12). ICV infusion of iRhom2-siRNA or ADAM17 neutralizing antibody for 2-weeks in DOCA-salt-treated mice resulted in a significant attenuation of BP (iRhom2-siRNA: 152 ±2 mmHg and ADAM17-Ab: 151 ±2 mmHg n=3/group, p<0.001). These data suggest that: 1) Selective silencing of iRhom2 from microglia is as potent as ADAM17 neutralization throughout the brain in lowering BP and 2) iRhom2 is a potential new therapeutic target for the treatment of salt-sensitive hypertension.

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