Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat

2007 ◽  
Vol 292 (2) ◽  
pp. F861-F867 ◽  
Author(s):  
Melvin R. Hayden ◽  
Nazif A. Chowdhury ◽  
Shawna A. Cooper ◽  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Proximal Tubule ◽  
Structural Damage ◽  
Kidney Tissue ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats ( P < 0.05) correlated strongly with albuminuria ( r2 = 0.83) and moderately with MDA ( r2 = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats ( P < 0.05). AT1R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-β-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

The Role of Endothelin and Oxidative Stress in the Slow Pressor Responses to Angiotensin II (ANG II).

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 685-685
Author(s):  
Clara M Ortiz-Ruiz ◽  
Elizabeth Sanabria ◽  
Melissa C Manriquez ◽  
Rodney J Bolterman ◽  
Luis A Juncos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Oxidant Stress ◽  
Vehicle Group ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Pressor Responses ◽  
Chronic Infusion ◽  
Group 2

44 Chronic infusion of subpressor doses of Ang II causes blood pressure to increase progressively over several days. The mechanisms underlying this response are unknown but may involve Ang II-induced generation of additional vasoconstrictor processes. In this study, we tested whether endothelin and/or oxidative stress are implicated in the slow pressor responses to Ang II. We infused either vehicle (group 1; n=6) or Ang II (group 2; n=5) intravenously at 5 ng/kg/min via osmotic pumps for 15 days into Sprague Dawley rats. In addition to the Ang II infusion, groups 3 and 4 (n=6 each) received 30 mg/kg/day of either losartan (an angiotensin AT 1 receptor blocker) or bosentan (a blocker of both endothelin receptors, ET A and ET B ) in their drinking water. We measured systolic blood pressure (SBP) during the infusion, and the levels of circulating Ang II and isoprostanes (a marker of oxidative stress) at the conclusion of the experiments. Rats infused with vehicle had no change in SBP (from 138±13 to 138±2 mmHg) and normal levels of Ang II (34.5±9 pg/ml) and isoprostanes (111±10 pg/ml). Ang II infusion increased SBP from 133±10 to 158±8 mmHg, as well as circulating levels of Ang II (144±65 pg/ml) and isoprostanes (156±19 pg/ml). Losartan treatment abolished Ang II induced increases in SBP (SBP went from 137±5 to 120±4 mmHg), and isoprostanes (115±15 pg/ml), without altering Ang II levels (101±30 pg/ml). Bosentan also blocked Ang II-induced increases in SBP (from 135±4 to 139±3) but did not alter the increased isoprostane levels (146±14 pg/ml). Surprisingly, bosentan blunted the increase in Ang II levels (51±10 pg/ml). In conclusion, low dose Ang II-induced increases in SBP and oxidant stress depend on the AT 1 receptor. Endothelin receptor blockade also reduces SBP, but it does so independently of reducing oxidative stress (as measured by isoprostanes).

Abstract 114: K+ Rich Diet During Angiotensin II Hypertension Reduces Renal Na-Cl Cotransporter and Phosphorylation, but Not Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Luciana C Veiras ◽  
Jiyang Han ◽  
Donna L Ralph ◽  
Alicia A McDonough
Keyword(s):  
Blood Pressure ◽  
Urine Volume ◽  
Weight Ratio ◽  
Distal Tubule ◽  
Reduce Blood Pressure ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
K Secretion ◽  
Pressure Natriuresis

During Ang II hypertension distal tubule Na-Cl Cotransporter (NCC) abundance and its activating phosphorylation (NCCp), as well as Epithelial Na+ channels (ENaC) abundance and activating cleavage are increased 1.5-3 fold. Fasting plasma [K+] is significantly lower in Ang II hypertension (3.3 ± 0.1 mM) versus controls (4.0 ± 0.1 mM), likely secondary to ENaC stimulation driving K+ secretion. The aim of this study was to test the hypothesis that doubling dietary K+ intake during Ang II infusion will lower NCC and NCCp abundance to increase Na+ delivery to ENaC to drive K+ excretion and reduce blood pressure. Methods: Male Sprague Dawley rats (225-250 g; n= 7-9/group) were treated over 2 weeks: 1) Control 1% K diet fed (C1K); 2) Ang II infused (400 ng/kg/min) 1% K diet fed (A1K); or 3) Ang II infused 2% K diet fed (A2K). Blood pressure (BP) was determined by tail cuff, electrolytes by flame photometry and transporters’ abundance by immunoblot of cortical homogenates. Results: As previously reported, Ang II infusion increased systolic BP (from 132 ± 5 to 197 ± 4 mmHg), urine volume (UV, 2.4 fold), urine Na+ (UNaV, 1.3 fold), heart /body weight ratio (1.23 fold) and clearance of endogenous Li+ (CLi, measures fluid volume leaving the proximal tubule, from 0.26 ± 0.02 to 0.51 ± 0.01 ml/min/kg) all evidence for pressure natriuresis. A2K rats exhibited normal plasma [K+] (4.6 ± 0.1 mM, unfasted), doubled urine K+ (UKV, from 0.20 to 0.44 mmol/hr), and increased CLi (to 0.8 ± 0.1 ml/min/kg) but UV, UNaV, cardiac hypertrophy and BP were unchanged versus the A1K group. As expected, NCC, NCCpS71 and NCCpT53 abundance increased in the A1K group to 1.5 ± 0.1, 2.9 ± 0.5 and 2.8 ± 0.4 fold versus C1K, respectively. As predicted by our hypothesis, when dietary K+ was doubled (A2K), Ang II infusion did not activate NCC, NCCpS71 nor NCCpT53 (0.91 ± 0.04, 1.3 ± 0.1 and 1.6 ± 0.2 fold versus C1K, respectively). ENaC subunit abundance and cleavage increased 1.5 to 3 fold in both A1K and A2K groups; ROMK was unaffected by Ang II or dietary K. In conclusion, evidence is presented that stimulation of NCC during Ang II hypertension is secondary to K+ deficiency driven by ENaC stimulation since doubling dietary K+ prevents the activation. The results also indicate that elevation in BP is independent of NCC activation

Abstract 41: Fructose Stimulates Na/H Exchanger 3 Activity and Enhances the Ability of Angiotensin II to Activate Na/H Exchanger 3 in the Proximal Tubule

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pablo Cabral ◽  
Nancy Hong ◽  
Jeffrey Garvin
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Physiological Saline ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Basal Rate ◽  
Low Concentrations ◽  
Sprague Dawley Rats ◽  
High Fructose ◽  
Salt Sensitive Hypertension

Consumption of high-fructose corn syrup as a sweetener has increased dramatically. Fructose has been implicated in the epidemic of diabetes, obesity and hypertension including salt-sensitive hypertension. However, the mechanisms are poorly understood. The proximal nephron reabsorbs 60-70% of the fluid and Na, and most of the filtered bicarbonate via Na/H exchanger 3. Enhanced proximal nephron transport has been implicated in several forms of hypertension. We hypothesized that fructose stimulates NHE3 activity and enhances the ability of angiotensin II (ANG II) to activate NHE3 in the proximal tubule. To test our hypothesis we isolated and perfused proximal tubules from Sprague Dawley rats. NHE3 activity was measured as the recovery of intracellular pH after an NH4Cl acid pulse using the pH sensitive dye BCECF. The rate of pH recovery was measured in Fluorescent Units per second (FU/sec). In the presence of a 5.5 mM glucose-containing physiological saline the basal rate of pH recovery was 3.1 ± 0.8 FU/sec. When the luminal solution was exchanged to a 0.6 mM glucose + 5 mM fructose-containing physiological saline in a second period, the rate of pH recovery increased to 5 ± 1 FU/sec (p<0.03, n=8).To study whether this effect was due to the addition of fructose or the removal of glucose to the lumen, we performed a separate set of experiments where 5 mM glucose was substituted for 5 mM fructose. In the presence of 0.6 mM glucose the basal rate of pH recovery was 3.6 ± 1.5 FU/sec. When 5 mM fructose was added the rate of pH recovery increased to 5.9 ± 2 FU/sec (p<0.02, n=5). Control experiments showed no differences between periods when 5 mm glucose was added back to the luminal perfusate. Finally, we tested the effect of low concentrations of ANG II in the presence or absence of luminal fructose. In the presence of 5.5 mM glucose, ANG II 10-12 M did not affect the rate of pH recovery (change: -1.1 ± 0.5 FU/sec, n=9). However, in the presence of 5 mM fructose, ANG II increased the rate of pH recovery (change: 4.0 ± 2.2 FU/sec, p< 0.03 n=6). We conclude that acute treatment with fructose stimulates NHE3 activity and enhances the ability of ANG II to activate NHE3 in the proximal tubule. These results may partially explain the mechanism by which a fructose diet induces hypertension.

scholarly journals Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats

2016 ◽  
Vol 310 (2) ◽  
pp. R115-R124 ◽  
Author(s):  
Kathryn R. Walsh ◽  
Jill T. Kuwabara ◽  
Joon W. Shim ◽  
Richard D. Wainford
Keyword(s):  
Blood Pressure ◽  
Sodium Chloride ◽  
Salt Sensitivity ◽  
Dietary Sodium ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sodium Chloride Cotransporter ◽  
Sprague Dawley Rats ◽  
Salt Sensitive Hypertension ◽  
The Impact

Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension.

scholarly journals Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat

2008 ◽  
Vol 295 (1) ◽  
pp. E103-E109 ◽  
Author(s):  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
Shawna A. Cooper ◽  
Vincent G. DeMarco ◽  
Melvin R. Hayden ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Myocardial Remodeling ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Nadph Oxidase Activity ◽  
Renin Inhibition

Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT1R) facilitates myocardial remodeling through NADPH oxidase-mediated generation of oxidative stress. Components of the renin-angiotensin system constitute an autocrine/paracrine unit in the myocardium, including renin, which is the rate-limiting step in the generation of Ang II. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo renin inhibition and/or AT1R blockade in a rodent model of chronically elevated tissue Ang II levels, the transgenic (mRen2)27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6- to 7-wk-old) heterozygous (+/−) male Ren2 and age-matched Sprague-Dawley rats were treated with the renin inhibitor aliskiren, which has high preferential affinity for human and mouse renin, an AT1R blocker, irbesartan, or placebo for 3 wk. Myocardial NADPH oxidase activity and immunostaining for NADPH oxidase subunits and 3-nitrotyrosine were evaluated and remodeling changes assessed by light and transmission electron microscopy. Blood pressure, myocardial NADPH oxidase activity and subunit immunostaining, 3-nitrotyrosine, perivascular fibrosis, mitochondrial content, and markers of activity were significantly increased in Ren2 compared with SD littermates. Both renin inhibition and blockade of the AT1R significantly attenuated cardiac functional and structural alterations, although irbesartan treatment resulted in greater reductions of both blood pressure and markers of oxidative stress. Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure.

scholarly journals Raspberry Consumption Attenuates Angiotensin II-Induced Oxidative Stress in the Subfornical Organ in Male Sprague-Dawley Rats

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 298-298
Author(s):  
Jasmynne Blacks ◽  
Ferdinand Althammer ◽  
Rami Najjar ◽  
Maureen Meister ◽  
Jessica Dahn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Subfornical Organ ◽  
Saline Control ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Funding Sources ◽  
Food Research ◽  
Food And Agriculture ◽  
Sprague Dawley Rats ◽  
Freeze Dried

Abstract Objectives To examine whether raspberry (RB) attenuates oxidative stress induced by angiotensin (Ang) II in the subfornical organ (SFO) of the brain in rats. Methods Male Sprague-Dawley rats were fed an AIN-93M diet with or without 10% w/w freeze-dried RB powder for seven weeks. At week 4, rats were implanted with subcutaneous osmotic minipumps that delivered 0.9% saline (Control) or Ang II (270 ng/kg body weight/day) for another three weeks. Brain region-specific tissue punches were collected from flash-frozen sections containing the SFO. NADPH oxidase (NOX) 2 and 4 and superoxide dismutase (SOD) 1 and 2 were measured in SFO using western blot. Results were analyzed using one-way ANOVA followed by Tukey post hoc test. Data were normalized to control and are expressed as means ± standard deviation. Results Ang II significantly increased NOX2 expression compared to control (1.24 ± 0.1, n = 5, vs 1.00 ± 0.07-fold, n = 3, P = 0.009) while RB supplementation significantly attenuated Ang II-induced increases in NOX2 (0.91 ± 0.05-fold, n = 4; P = 0.0006). Ang II also increased NOX4 expression compared to control (2.11 ± 1.2, n = 9, vs 0.98 ± 0.4-fold, n = 6, P = 0.04), but RB supplementation did not significantly attenuate this effect (1.30 ± 0.36-fold, n = 10, P = 0.11). RB increased expression of SOD1 (1.52 ± 0.20-fold, n = 4) compared to control (1.00 ± 0.15-fold, n = 3, P = 0.009) and Ang II alone (1.08 ± 0.16-fold, n = 5, P = 0.01). On the other hand, Ang II treatment decreased SOD2 expression compared to control (0.62 ± 0.05, n = 5, vs 1.00 ± 0.09-fold, n = 3, P = 0.0001), but the RB supplementation did not prevent this effect (0.72 ± 0.07-fold, n = 4, P = 0.16). Conclusions Our findings suggest that RB supplementation decreases Ang II-induced oxidative stress in the SFO by decreasing NOX2 and increasing SOD1 expression. Future investigations are warranted to elucidate the effects of RB on oxidative stress pathways in the SFO. Funding Sources This work was supported by the Agriculture and Food Research Initiative (grant no. 2019–67,017-29,257/project accession no. 1,018,642) from the USDA National Institute of Food and Agriculture.

scholarly journals Combined Suppression of the Intrarenal and Circulating Vasoconstrictor Renin-ACE-ANG II Axis and Augmentation of the Vasodilator ACE2-ANG 1-7-Mas Axis Attenuates the Systemic Hypertension in Ren-2 Transgenic Rats Exposed to Chronic Hypoxia

2015 ◽  
pp. 11-24 ◽  
Author(s):  
L. ČERVENKA ◽  
J. BÍBOVÁ ◽  
Z. HUSKOVÁ ◽  
Z. VAŇOURKOVÁ ◽  
H. J. KRAMER ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Hypoxia ◽  
Substantial Reduction ◽  
Kidney Tissue ◽  
Renin Angiotensin System ◽  
Systemic Hypertension ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Pressure Lowering

The aim of the present study was to test the hypothesis that chronic hypoxia would aggravate hypertension in Ren-2 transgenic rats (TGR), a well-defined monogenetic model of hypertension with increased activity of endogenous renin-angiotensin system (RAS). Systolic blood pressure (SBP) in conscious rats and mean arterial pressure (MAP) in anesthetized TGR and normotensive Hannover Sprague-Dawley (HanSD) rats were determined under normoxia that was either continuous or interrupted by two weeks´ hypoxia. Expression, activities and concentrations of individual components of RAS were studied in plasma and kidney of TGR and HanSD rats under normoxic conditions and after exposure to chronic hypoxia. In HanSD rats two weeks´ exposure to chronic hypoxia did not alter SBP and MAP. Surprisingly, in TGR it decreased markedly SBP and MAP; this was associated with substantial reduction in plasma and kidney renin activities and also of angiotensin II (ANG II) levels, without altering angiotensin-converting enzyme (ACE) activities. Simultaneously, in TGR the exposure to hypoxia increased kidney ACE type 2 (ACE2) activity and angiotensin 1-7 (ANG 1-7) concentrations as compared with TGR under continuous normoxia. Based on these results, we propose that suppression of the hypertensiogenic ACE-ANG II axis in the circulation and kidney tissue, combined with augmentation of the intrarenal vasodilator ACE2-ANG 1-7 axis, is the main mechanism responsible for the blood pressure-lowering effects of chronic hypoxia in TGR.

Subfornical organ and cardiovascular influences on identified septal neurons

1988 ◽  
Vol 254 (3) ◽  
pp. R544-R551 ◽  
Author(s):  
S. D. Donevan ◽  
A. V. Ferguson
Keyword(s):  
Blood Pressure ◽  
Medial Septum ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Diagonal Band ◽  
Sprague Dawley Rats ◽  
Relay Neuron ◽  
Afferent Information ◽  
Septal Neurons

We have identified, in urethan-anesthetized male Sprague-Dawley rats, a polysynaptic pathway connecting the subfornical organ (SFO) with the paraventricular nucleus (PVN) with a relay neuron in the medial septum-diagonal band of Broca (MS-DBB). Extracellular recordings were obtained from 136 MS-DBB neurons antidromically identified as projecting to the PVN. SFO stimulation orthodromically activated 79% of these cells (mean latency, 21.2 +/- 0.6 ms; mean duration, 6.0 +/- 0.2 ms), whereas stimulation in the fornix or hippocampal commissure had no effect. Of 35 identified MS-DBB neurons tested with systemic angiotensin II (ANG II), eight showed increases and six decreases in excitability that coincided with the ANG II-induced increase in blood pressure. To determine whether such changes were blood pressure related, 23 of the 35 identified MS-DBB neurons tested with ANG II were tested with systemic epinephrine. In every case the effect of epinephrine was similar to that of ANG II. These findings suggest that neurons in the MS-DBB receive afferent information from the SFO and the cardiovascular system. These cells in turn may activate neurons involved in the control of a variety of autonomic functions.

Empagliflozin treatment does not affect the hypertensive response to Ang II administration to rats but decreases oxidative stress in the arterial wall, and endothelial and cardiac dysfunction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Bruckert ◽  
L Remila ◽  
K Matsushita ◽  
C Auger ◽  
U Houngue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Left Ventricle ◽  
Cardiac Function ◽  
Systolic Blood Pressure ◽  
Sglt2 Inhibitor ◽  
Treated Group ◽  
Funding Source ◽  
Ang Ii

Abstract Background Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection in type 2 diabetes patients with established cardiovascular disease independently of glycemic control. Angiotensin II (Ang II) and H2O2 have been shown to be strong inducers of the expression of SGLT2 and 1 in endothelial cells promoting oxidative stress and endothelial dysfunction. Purpose This study examined the cardiovascular protective effect of empagliflozin (empa) in a normoglycemic experimental model of hypertension in the rat. Methods Male Wistar rats received empa (30 mg/kg/day) provided in the diet for 5 weeks. After 1 week, rats underwent sham surgery (sham rats) or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/d) for 4 weeks. Systolic blood pressure (SBP) was assessed by sphygmomanometry, the cardiac function using echocardiography, the expression level of target proteins by immunofluorescence staining, and the level of oxidative stress using dihydroethidium staining. Results Angiotensin II administration increased systolic blood pressure from about 130 to 180 mmHg, which was not affected by the empa treatment. The 4-week Ang II treatment did not significantly affect the systolic cardiac function (cardiac output, left ventricle ejection fraction) but impaired the diastolic function as indicated by a reduced E' and IVRT values, and an increased E/E' value. The Ang II treatment increased significantly the heart and right ventricle weight whereas the left ventricle + septum weight was slightly but not significantly increased. No such functional and structural changes were observed in the Ang II + empa treatment group. An increased immunofluorescence eNOS signal in the endothelium, and a higher level of ROS throughout the aorta wall were observed in the Ang II-treated group, both of which were significantly reduced in the empa + Ang II-treated group. In the Ang II-treated group, the high level of oxidative stress in the aorta was significantly reduced by the AT1 receptor antagonist losartan, the NADPH oxidase inhibitor VAS-2871, the eNOS inhibitor NG-nitro-L-arginine and also to a greater extent by the selective SGLT2 inhibitor empa compared to the dual SGLT1/2 inhibitor sotagliflozin. Conclusion(s) The present findings indicate that although the empa treatment did not affect the hypertensive response of rats to Ang II, the SGLT2 inhibitor prevented the deleterious impact of Ang II on the diastolic cardiac function and remodeling, and the upregulation of eNOS expression and oxidative stress in the aorta wall. Thus, these findings highlight the protective potential of empa on the cardiovascular system in a normoglycemic hypertensive experimental model. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH & Co KG (Biberach an der Riss, Germany)

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