Loss of Soluble (Pro)renin Receptor Attenuates Angiotensin-II Induced Hypertension and Renal Injury

2021 ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Caitlin S Peterson ◽  
Chunyan Hu ◽  
William Wheatley ◽  
...  
Keyword(s):  
Renal Injury ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Gene Encoding ◽  
Undetectable Plasma ◽  
Induced Hypertension ◽  
Survival And Development ◽  
Cellular Domain ◽  
Renal Tubular

Rationale: Cleavage of the extra-cellular domain of the (pro)renin receptor (PRR) yields a soluble fragment (sPRR). Although changes in plasma sPRR levels have been reported in hypertension, the causal role of sPRR in blood pressure (BP) regulation is unknown. Objective: Determine the role of sPRR in BP regulation at baseline and following Ang-II induced hypertension. Methods and Results: CRISPR-Cas9 was used to mutate the cleavage site of the PRR such that sPRR is not generated. Because the gene encoding PRR is on the X-chromosome and male mutant sPRR mice are infertile, only male mice were studied. Mutant sPRR mice had virtually undetectable plasma sPRR levels compared to littermate controls. Mutant sPRR mice had normal survival and development and no apparent histological abnormalities in the kidney, heart or aorta despite lower body weight. During normal Na+ intake, no differences in food or water intake, urinary water or Na+ excretion, or acid-base status were observed between control and mutant sPRR mice. Compared to controls, mutant sPRR mice had lower BP at baseline and an attenuated hypertensive response to 2 weeks of Ang-II infusion (400 ng/kg/min) which was partially reversed by infusion of mouse recombinant sPRR. Mutant sPRR mice also had lower albuminuria, renal tubular injury and oxidative stress relative to control mice post Ang-II infusion. Further, mesenteric arteries from mutant sPRR mice displayed reduced Ang-II-induced vasocontraction and greater acetylcholine, but not sodium nitroprusside, evoked vasorelaxation under baseline conditions. Conclusions: Loss of sPRR reduces BP at baseline and decreases Ang-II induced hypertension and renal injury. These effects of sPRR loss are associated with greater endothelium-dependent but not independent vasorelaxation of resistance-sized arteries.

Reduced expression of SKCa and IKCa channel proteins in rat small mesenteric arteries during angiotensin II-induced hypertension

2007 ◽  
Vol 292 (5) ◽  
pp. H2275-H2284 ◽  
Author(s):  
Rob H. P. Hilgers ◽  
R. Clinton Webb
Keyword(s):  
Angiotensin Ii ◽  
Channel Blocker ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Expression Levels ◽  
Protein Levels ◽  
Channel Proteins ◽  
Induced Hypertension ◽  
Relaxation Responses

Ca2+-activated K+ channels (KCa), in particular, the small and intermediate KCa (SKCa and IKCa, respectively) channels, are key players in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in small arteries. Hypertension is characterized by an endothelial dysfunction, possibly via reduced EDHF release and/or function. We hypothesize that during angiotensin II (14 days)-induced hypertension (ANG II-14d), the contribution of SKCa and IKCa channels in ACh-induced relaxations is reduced due to decreased expression of SKCa and IKCa channel proteins in rat small mesenteric arteries (MAs). Nitric oxide- and prostacyclin-independent vasorelaxation to ACh was similar in small MAs of sham-operated and ANG II-14d rats. Catalase had no inhibitory effects on these relaxations. The highly selective SKCa channel blocker UCL-1684 almost completely blocked these responses in MAs of sham-operated rats but partially in MAs of ANG II-14d rats. These changes were pressure dependent since UCL-1684 caused a greater inhibition in MAs of 1-day ANG II-treated normotensive rats compared with ANG II-14d rats. Expression levels of both mRNA and protein SK3 were significantly reduced in MAs of ANG II-14d rats. The IKCa channel blocker 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) resulted in comparable reductions in the relaxation responses to ACh in MAs of sham-operated and ANG II-14d rats. Relative mRNA expression levels of IK1 were significantly reduced in MAs of ANG II-14d rats, whereas protein levels of IK1 were not but tended to be lower in MAs of ANG II-14d rats. The findings demonstrate that EDHF-like responses are not compromised in a situation of reduced functional activity and expression of SK3 channels in small MAs of ANG II-induced hypertensive rats. The role of IK1 channels is less clear but might compensate for reduced SK3 activity.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

Expression of Cell Cycle Proteins P21 waf1/Cip1 , P27 kip1 , Cyclin D1 and CDK4 in Blood Vessels of Angiotensin II-Infused Rats. Role of AT 1 Receptors.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 707-707
Author(s):  
Quy N Diep ◽  
Mohammed El Mabrouk ◽  
Rhian M Touyz ◽  
Ernesto L Schiffrin
Keyword(s):  
Cell Cycle ◽  
Angiotensin Ii ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Blood Vessels ◽  
Thymidine Incorporation ◽  
Mesenteric Arteries ◽  
Ang Ii

P79 Angiotensin II (Ang II) is an important modulator of cell growth via AT 1 receptors, as demonstrated both in vivo and in vitro . Here, we investigated the role of different proteins involved in the cell cycle, including cyclin D1, cyclin-dependent kinase 4 (cdk4) and cdk inhibitors p21 and p27 in blood vessels of Ang II-infused rats and the effect therein of the AT 1 receptor antagonist losartan. Male Sprague Dawley rats were infused for 7 days with Ang II (120 ng/kg/min s.c.) and/or treated with losartan (10 mg/kg/day orally). DNA synthesis in mesenteric arteries was evaluated by radiolabeled 3 H-thymidine incorporation. The expression of p21, p27, cyclin D1, cdk4 and E2F, which play critical roles during G1-phase of the cell cycle process, was examined by Western blot analysis. Tail cuff systolic blood pressure (mmHg) was elevated (p<0.05, n=9) in Ang II-infused rats (161.3±8.2) vs. controls (110.1±5.3) and normalized by losartan (104.4±3.2). Radiolabeled 3 H-thymidine incorporation (cpm/100 μg DNA) showed that Ang II-infusion significantly increased DNA synthesis (152±5 vs. 102±6, p<0.05). Expression of p21 and p27 was significantly decreased in the Ang II group to 23.2±10.4% and 10.3±5.3% of controls, respectively, whereas expression of cyclin D1 and cdk4 was significantly increased in the Ang II group to 213.7±8% and 263.6±37% of controls, respectively. These effects induced by Ang II infusion was normalized in the presence of losartan. Ang II had no effect on the expression of E2F. Thus, when AT 1 receptors are stimulated in vivo , DNA synthesis is enhanced in blood vessels by activation of cyclin D1 and cdk4. Reduction in cell cycle kinase inhibitors p21 and p27 may contribute to activation of growth induced by in vivo AT 1 receptor stimulation.

Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake

2001 ◽  
Vol 281 (5) ◽  
pp. H2218-H2225 ◽  
Author(s):  
Jennifer R. Ballew ◽  
Gregory D. Fink
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Salt Intake ◽  
Receptor Activation ◽  
Salt Sensitivity ◽  
Male Rats ◽  
Ang Ii ◽  
High Salt Intake ◽  
Induced Hypertension

We showed recently that endothelin (ET)A receptors are involved in the salt sensitivity of ANG II-induced hypertension. The objective of this current study was to characterize the role of endothelin ETB receptor activation in the same model. Male rats on fixed normal (2 meq/day) or high (6 meq/day) salt intake received a continuous intravenous infusion of ANG II or salt only for 15 days. During the middle 5 days of the infusion period, rats were given either the selective ETB receptor antagonist A-192621 or the nonselective endothelin receptor antagonist A-182086 (both at 24 mg · kg−1 · day−1intra-arterially). Infusion of ANG II caused a greater rise in arterial pressure in rats on high-salt intake. The administration of A-192621 increased arterial pressure further in all rats. The chronic hypertensive effect of A-192621 was not significantly affected by salt intake or ANG II. The administration of A-182086 lowered arterial pressure chronically only in rats on normal salt intake receiving ANG II. Thus the salt sensitivity of ANG II-induced hypertension is not caused by changes in ETB receptor function.

scholarly journals Genetic and genomic evidence for an important role of the Na+/H+ exchanger 3 in blood pressure regulation and angiotensin II-induced hypertension

2019 ◽  
Vol 51 (4) ◽  
pp. 97-108 ◽  
Author(s):  
Xiao C. Li ◽  
Xiaowen Zheng ◽  
Xu Chen ◽  
Chunling Zhao ◽  
Dongmin Zhu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Pressure Regulation ◽  
Blood Pressure Homeostasis ◽  
Induced Hypertension ◽  
Basal Blood Pressure

The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) and sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) are two of the most important Na+ transporters in the proximal tubules of the kidney. On the apical membrane side, NHE3 primarily mediates the entry of Na+ into and the exit of H+ from the proximal tubules, directly and indirectly being responsible for reabsorbing ~50% of filtered Na+ in the proximal tubules of the kidney. On the basolateral membrane side, Na+/K+-ATPase serves as a powerful engine driving Na+ out of, while pumping K+ into the proximal tubules against their concentration gradients. While the roles of NHE3 and Na+/K+-ATPase in proximal tubular Na+ transport under in vitro conditions are well recognized, their respective contributions to the basal blood pressure regulation and angiotensin II (ANG II)-induced hypertension remain poorly understood. Recently, we have been fortunate to be able to use genetically modified mouse models with global, kidney- or proximal tubule-specific deletion of NHE3 to directly determine the cause and effect relationship between NHE3, basal blood pressure homeostasis, and ANG II-induced hypertension at the whole body, kidney and/or proximal tubule levels. The purpose of this article is to review the genetic and genomic evidence for an important role of NHE3 with a focus in the regulation of basal blood pressure and ANG II-induced hypertension, as we learned from studies using global, kidney- or proximal tubule-specific NHE3 knockout mice. We hypothesize that NHE3 in the proximal tubules is necessary for maintaining basal blood pressure homeostasis and the development of ANG II-induced hypertension.

scholarly journals Asymmetric dimethylarginine in angiotensin II-induced hypertension

2010 ◽  
Vol 298 (3) ◽  
pp. R740-R746 ◽  
Author(s):  
Jennifer M. Sasser ◽  
Natasha C. Moningka ◽  
Mark W. Cunningham ◽  
Byron Croker ◽  
Chris Baylis
Keyword(s):  
Nitric Oxide ◽  
Renal Injury ◽  
Asymmetric Dimethylarginine ◽  
Renal Cortex ◽  
Interstitial Fibrosis ◽  
Glomerular Sclerosis ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Plasma Adma ◽  
Induced Hypertension

Recent studies have shown that asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is increased in hypertension and chronic kidney disease. However, little is known about the effects of hypertension per se on ADMA metabolism. The purpose of this study was to test the hypothesis that ANG II-induced hypertension, in the absence of renal injury, is associated with increased oxidative stress and plasma and renal cortex ADMA levels in rats. Male Sprague-Dawley rats were treated with ANG II at 200 ng·kg−1·min−1 sc (by minipump) for 1 or 3 wk or at 400 ng·kg−1·min−1 for 6 wk. Mean arterial pressure was increased after 3 and 6 wk of ANG II; however, renal injury (proteinuria, glomerular sclerosis, and interstitial fibrosis) was only evident after 6 wk of treatment. Plasma thiobarbituric acid reactive substances concentration and renal cortex p22phox protein abundance were increased early (1 and 3 wk), but urinary excretion of isoprostane and H2O2 was only increased after 6 wk of ANG II. An increased in plasma ADMA after 6 wk of ANG II was associated with increased lung protein arginine methyltransferase-1 abundance and decreased renal cortex dimethylarginine dimethylaminohydrolase activity. No changes in renal cortex ADMA were observed. ANG II hypertension in the absence of renal injury is not associated with increased ADMA; however, when the severity and duration of the treatment were increased, plasma ADMA increased. These data suggest that elevated blood pressure alone, for up to 3 wk, in the absence of renal injury does not play an important role in the regulation of ADMA. However, the presence of renal injury and sustained hypertension for 6 wk increases ADMA levels and contributes to nitric oxide deficiency and cardiovascular disease.

Abstract 101: Cardiac Deleterious Role of Galectin-3 in Chronic Angiotensin-II Induced Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Germán E González ◽  
Nour-Eddine Rhaleb ◽  
Xiao- P Yang ◽  
Oscar A Carretero
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Carbohydrate Binding ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Galectin 3

We previously described that chronic infusion with Angiotensin II (Ang II) increases cardiac Galectin-3 (Gal-3) expression, a carbohydrate-binding lectin present on macrophages. Also, Gal-3 was proposed to be a powerful predictor for mortality in patients with heart failure. Nevertheless, the role of Gal-3 in the pathogenesis of end organ damage (EOD) in hypertension is unknown. Here, we hypothesized that in Ang II-induced hypertension, genetic deletion of Gal-3 prevents innate immunity, EOD, and left ventricular (LV) dysfunction. Male C57 and Gal-3 KO mice were infused with vehicle (V) or Ang II (90 ng/min; s.c.) for 8 weeks and divided into: 1) C57 + V; 2) Gal-3 KO + V; 3) C57 + Ang II and 4) Gal-3 KO + Ang II. Systolic blood pressure (SBP) was measured by plestimography weekly. At 8 week, we evaluated 1) LV ejection fraction (EF) by echocardiography; 2) cardiac hypertrophy by LV weight/tibia length; 3) cardiac fibrosis by picrosirius red staining; 4) infiltrated macrophages by CD68+ staining; 5) ICAM-1 protein expression by Western blot; and 6) serum interleukin (IL)-6 by ELISA. We found that despite a similar increase in SBP and LV hypertrophy in both strains on Ang II, Gal-3 KO mice had better reserved EF and decreased inflammatory and fibrotic responses (see Table). Results: (MEAN ± SEM at 8 w) *p<0.05 C57+Ang II and Gal-3 KO+Ang II vs C57+V; ‡ p<0.05 Gal-3 KO+Ang II vs C57+Ang II. Conclusion: In Ang II-induced hypertension, deletion of Gal-3 prevents EOD and LV systolic dysfunction without altering blood pressure and LV hypertrophy. This study indicates that the deleterious effects of Ang II could be in part mediated by Gal-3, which enhanced inflammation and fibrosis.

Abstract 422: Role of Brain Salt-inducible Kinase 1 in Responses to Central Sodium in Salt-induced Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Bing S Huang ◽  
Roselyn A White ◽  
Frans H Leenen
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Specific Protein ◽  
Feedback Mechanism ◽  
Ang Ii ◽  
High Salt Diet ◽  
Pressor Responses ◽  
Induced Hypertension ◽  
Protein Kinase C Inhibitor

In Dahl salt sensitive (S) rats, sympatho-excitatory and pressor responses to CSF Na + are enhanced. Salt-inducible kinase 1 (SIK1) increases Na + /K + -ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of sympatho-excitatory and pressor responses to Na + in the brain. Icv injection of the protein kinase inhibitor staurosporine (staur, 5ng) to inhibit SIK1 similarly enhanced renal sympathetic nerve activity (RSNA), BP and HR responses to icv infusion of Na + -rich aCSF in Wistar and salt-resistant Dahl SS.BN13. The enhancement in Dahl S rats was only 1/3 of that in other strains. Staur had no effect on BP responses to icv Ang II or carbachol, whereas the specific protein kinase C inhibitor GF109203X attenuated pressor responses to icv Na + -rich aCSF or Ang II. Hypothalamic SIK1 protein and activity, measured by Western blot and phosphocellulose binding technique, were lower in Dahl S vs SS.BN13 rats after high salt diet for 2 weeks. Staur at 5-50 nM inhibited SIK1 activity in a dose-related manner. These data suggest that the SIK1 -Na + /K + -ATPase network in neurons acts as a feedback mechanism to attenuate sympatho-excitatory and pressor responses to increases in brain [Na + ]. Lower neuronal SIK1 protein expression and activity in Dahl S rats may contribute to enhanced responses to CSF Na + and thereby to their salt-induced hypertension. Data= means±SE (n=4-7). * p<0.05, vs. SS.BN13 or Wistar rats.

Abstract 46: FOXP3+ T Regulatory Lymphocytes Counteract Angiotensin II-Induced Vascular Injury

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Muhammad Oneeb Rehman Mian ◽  
Tlili Barhoumi ◽  
Marie Briet ◽  
Adriana Cristina Ene ◽  
Asia Rehman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Endothelial Dysfunction ◽  
T Lymphocytes ◽  
Vascular Injury ◽  
Mesenteric Arteries ◽  
Ros Production ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Regulatory Lymphocytes

Introduction: T lymphocytes participate in the low-grade inflammatory response that causes vascular injury in angiotensin (Ang) II-induced hypertension. Ang II-induced hypertension and endothelial dysfunction are blunted in T and B lymphocyte-deficient ( Rag1 -/- ) mice, and restored with reconstitution of T cells. However, the role of T regulatory lymphocytes (Treg) in Ang II-induced vascular injury is unclear. We hypothesized that adoptive transfer of FOXP3-deficient (Scurfy) T lymphocytes vs. wild-type (WT) cells will exacerbate Ang II-induced vascular damage in Rag1 -/- mice. Methods: Eleven-week old male Rag1 -/- mice were injected IV with PBS/2% FBS (control), 10 7 WT or Scurfy T lymphocytes, and 2 weeks later underwent sham surgery or were infused with Ang II (490 ng/kg/min, s.c.) using mini-osmotic pumps for 14 days (n=3-8). Systolic (SBP) and diastolic (DBP) blood pressure were measured by telemetry. Vascular function and structure were assessed in second order mesenteric arteries by pressurized myography. Reactive oxygen species (ROS) production and fibronectin and collagen I and III expression were determined in aorta. Results: Ang II induced a 40 mmHg SBP rise in Rag1 -/- mice for all treatment groups, but DBP rise was ~10 mmHg greater for WT and Scurfy T cell-injected mice than for control mice ( P <0.01). Adoptive transfer of WT T cells restored Ang II induced-endothelial dysfunction in mesenteric arteries ( P <0.05), which was exaggerated in Scurfy T cell-injected mice ( P <0.01). Ang II induced a greater increase in ROS production in aortic perivascular fat of Scurfy T cell-injected mice compared to WT T cell-injected mice ( P <0.05). Ang II induced mesenteric artery stiffness ( P <0.01) and hypertrophic remodeling ( P <0.05) in control and Scurfy T cell-injected mice, but not in WT T cell-injected mice. Ang II increased fibronectin expression to a greater extent in the aorta of control and Scurfy T cell-injected mice compared to WT T cell-injected mice ( P <0.01). Collagen I and III content was greater in the aorta of control and Scurfy T cell-injected mice than in WT T cell-injected mice ( P <0.01), but expression was unaltered by Ang II treatment. Conclusion: Foxp3+ T regulatory lymphocytes have a protective role against Ang II-induced vascular remodeling.

Abstract 011: An Orally Absorbable Potent NHE3 Inhibitor Attenuates Angiotensin II-induced Hypertension Primarily by Inhibiting NHE3 in the Proximal Tubule of the Kidney

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Hoang Nguyen ◽  
Jia L Zhuo
Keyword(s):  
Proximal Tubule ◽  
The Body ◽  
High Salt ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Small Intestines ◽  
Orally Active ◽  
Nhe3 Inhibitor

We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global ( Nhe3 -/- ) and Nhe3 -/- mice with transgenic rescue of the NHE3 gene selectively in small intestines (tg Nhe3 -/- ), suggesting an important role of NHE3 in the development of ANG II-dependent hypertension. In this study, we specifically tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubules of the kidney attenuates ANG II-dependent hypertension induced by a low and slow pressor dose of ANG II supplemented with a high salt diet. Overall, 9 groups (n=5-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via minipump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase systolic blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116 ± 2 mmHg to 140 ± 2 mmHg ( p <0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147 ± 4 mmHg ( p <0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125 ± 4 mmHg in ANG II-infused mice ( p <0.01), and to 134 ± 6 mmHg in ANG II-infused mice supplemented with 2% NaCl ( p <0.01), respectively. Further treatment with AVE0657 and losartan, an AT 1 receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115 ± 5 mmHg, p <0.01). In the kidney, AVE0657 significantly increased 24h urinary Na + excretion from 157.1 ± 6.7 to 207.7 ± 8.1 μmol/24h ( p <0.01) without altering 24h urine excretion or SBP. Furthermore, AVE0657 did not significantly alter 24 h fecal Na + excretion in non ANG II-infused (4.99 ± 0.37 μmol/24h, n.s.) or ANG II-infused mice (4.19 ± 0.67 μmol/24h, n.s.), compared with control (4.02 ± 0.20 μmol/24h, n.s. ) or global Nhe3 -/- mice (50.8 ± 0.8 μmol/24h, p <0.01). Since small intestines in the gut and the proximal tubules of the kidney express the vast majority of NHE3 in the body, these results provide preclinical evidence and perspectives that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to prevent and treat hypertension induced by ANG II and a high salt, mainly by inhibiting NHE3 in the proximal tubule of the kidney.

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