Abstract MP42: Metabolomic Study To Identify Common Metabolites In Two Different Mouse Models Of Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Gaurav Baranwal ◽  
RACHEL PILLA ◽  
Bethany Goodlett ◽  
Arul Jayaraman ◽  
Joseph M Rutkowski ◽  
...  
Keyword(s):  
Mouse Models ◽  
American Heart ◽  
Heart Association ◽  
Experimental Hypertension ◽  
High Salt Diet ◽  
Salt Diet ◽  
Serum Metabolites ◽  
Induced Hypertension ◽  
Metabolomic Study

Metabolomic Study to Identify Common Metabolites in Two Different Mouse Models of Hypertension Recent studies have reflected the importance of the body’s microbiome and associated metabolites and their changes in hypertension. In the current study, we hypothesized that metabolite changes common between hypertension models may unify hypertension’s pathophysiology with respect to metabolites. Two different mice models of experimental hypertension were used in the study: (1) L-arginine methyl ester hydrochloride (L-NAME)/High salt diet induced hypertension (LSHTN) and (2) angiotensin II induced hypertension (AHTN). Untargeted global metabolomics analysis in serum and urine samples were performed to identify common metabolites altered across both hypertensive models, and the resulting data were analyzed using MetaboAnalyst software and compared to control mice. A list of metabolites that were altered significantly in both models of hypertension were identified. A total of 41 serum metabolites were identified as being altered significantly in any hypertensive model compared to controls. Of these, however, only 4 were increased significantly, and 10 were decreased significantly in common across both hypertensive groups. In the urine, 6 metabolites were altered significantly in any hypertensive group with respect to control, however, 0 of them were common between the hypertensive groups. These findings demonstrate that a modest, but potentially important, number of serum metabolites are commonly altered between experimental hypertension models. Further studies to understand the role of these identified metabolites may lead to a greater understanding of the association between gut dysbiosis and hypertension. Submitted to American Heart Association Council on Hypertension Scientific Sessions (September 27-29, 2021, Virtual)Abstract#: 21-HBPR-A-578-AHA

scholarly journals Common Metabolites in Two Different Hypertensive Mouse Models: A Serum and Urine Metabolome Study

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1387
Author(s):  
Gaurav Baranwal ◽  
Rachel Pilla ◽  
Bethany L. Goodlett ◽  
Aja K. Coleman ◽  
Cristina M. Arenaz ◽  
...  
Keyword(s):  
Mouse Models ◽  
Active Role ◽  
Experimental Hypertension ◽  
High Salt Diet ◽  
Salt Diet ◽  
Serum Metabolites ◽  
Gut Dysbiosis ◽  
Induced Hypertension ◽  
Metabolomics Analysis ◽  
Serum And Urine

Recent metabolomics studies have identified a wide array of microbial metabolites and metabolite pathways that are significantly altered in hypertension. However, whether these metabolites play an active role in pathogenesis of hypertension or are altered because of this has yet to be determined. In the current study, we hypothesized that metabolite changes common between hypertension models may unify hypertension’s pathophysiology with respect to metabolites. We utilized two common mouse models of experimental hypertension: L-arginine methyl ester hydrochloride (L-NAME)/high-salt-diet-induced hypertension (LSHTN) and angiotensin II induced hypertension (AHTN). To identify common metabolites that were altered across both models, we performed untargeted global metabolomics analysis in serum and urine and the resulting data were analyzed using MetaboAnalyst software and compared to control mice. A total of 41 serum metabolites were identified as being significantly altered in any hypertensive model compared to the controls. Of these compounds, 14 were commonly changed in both hypertensive groups, with 4 significantly increased and 10 significantly decreased. In the urine, six metabolites were significantly altered in any hypertensive group with respect to the control; however, none of them were common between the hypertensive groups. These findings demonstrate that a modest, but potentially important, number of serum metabolites are commonly altered between experimental hypertension models. Further studies of the newly identified metabolites from this untargeted metabolomics analysis may lead to a greater understanding of the association between gut dysbiosis and hypertension.

scholarly journals Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

2009 ◽  
Vol 296 (4) ◽  
pp. R994-R1000 ◽  
Author(s):  
Bing S. Huang ◽  
Roselyn A. White ◽  
Arco Y. Jeng ◽  
Frans H. H. Leenen
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Aldosterone Synthase ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
Synthase Inhibitor ◽  
The Brain

In Dahl salt-sensitive (S) rats, high salt intake increases cerebrospinal fluid (CSF) Na+ concentration ([Na+]) and blood pressure (BP). Intracerebroventricular (ICV) infusion of a mineralocorticoid receptor (MR) blocker prevents the hypertension. To assess the role of aldosterone locally produced in the brain, we evaluated the effects of chronic central blockade with the aldosterone synthase inhibitor FAD286 and the MR blocker spironolactone on changes in aldosterone and corticosterone content in the hypothalamus and the increase in CSF [Na+] and hypertension induced by high salt intake in Dahl S rats. After 4 wk of high salt intake, plasma aldosterone and corticosterone were not changed, but hypothalamic aldosterone increased by ∼35% and corticosterone tended to increase in Dahl S rats, whereas both steroids decreased by ∼65% in Dahl salt-resistant rats. In Dahl S rats fed the high-salt diet, ICV infusion of FAD286 or spironolactone did not affect the increase in CSF [Na+]. ICV infusion of FAD286 prevented the increase in hypothalamic aldosterone and 30 mmHg of the 50-mmHg BP increase induced by high salt intake. ICV infusion of spironolactone fully prevented the salt-induced hypertension. These results suggest that, in Dahl S rats, high salt intake increases aldosterone synthesis in the hypothalamus and aldosterone acts as the main MR agonist activating central pathways contributing to salt-induced hypertension.

Abstract 107: Role of Nox4 in the Control of ENaC Activity in Dahl SS Rats During the Development of Salt-induced Hypertension and Diabetic Nephropathy

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Tengis S Pavlov ◽  
Daria V Ilatovskaya ◽  
Gregory Blass ◽  
Oleg Palygin ◽  
Vladislav Levchenko ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
High Salt ◽  
Diet Change ◽  
Open Probability ◽  
High Salt Diet ◽  
Salt Diet ◽  
Nadph Oxidase 4 ◽  
Induced Hypertension

Dahl salt sensitive (SS) rat is a well-established model for studying salt-induced hypertension and associated kidney injury. We and others have previously shown that salt-sensitive hypertension is accompanied by increased renal production of reactive oxygen species (ROS) and excessive activity of ENaC in the distal nephron. To investigate role of ROS, and specifically NADPH oxidase 4 (Nox4), a primary source of ROS in the kidney, involved in the regulation of ENaC activity during the development of SS hypertension and type 1 diabetes, we performed patch clamp analysis in the cortical collecting ducts of Dahl SS rats and SS rats lacking Nox4 (Nox4 -/- ). We found that SS rats fed a 4% NaCl diet have significantly elevated ENaC activity even 3 days post diet change. ENaC activity (NP o ) was 0.57±0.08, 1.32±0.3 and 1.69±0.06 before, 3 days and 3 weeks after high salt diet, respectively. In contrast, ENaC activity was not significantly different in SS Nox4-/- animals after high salt diet. To study the role of Nox4 in hyperglycemic conditions, diabetes was induced in 6 weeks old male wild type or Nox4 -/- rats with a single i.p. injection of STZ. We found that ENaC activity in the animals that were hyperglycemic for 11 weeks was elevated compared to control rats (0.71±0.10 and 1.27±0.2; p<0.05) and this effect was mediated via changes in channel open probability. Nox4 deficiency blunts the effect of hyperglycemia on ENaC activity (in STZ-treated animals open probability significantly increased from 0.43±0.06 to 0.86±0.07 in WT rats, but in the Nox4 -/- group did not change: P o was 0.51±0.06 and 0.51±0.07, respectively) that delineates the importance of Nox4-mediated ROS production for regulation of ENaC open probability. Taken together, our data indicate that ENaC activity in Dahl SS rats is elevated following a change of salt diet (3 days and 3 weeks at high salt) and after the development of type 1 diabetes. Furthermore, Nox4 plays a crucial role in these effects of high salt and hyperglycemia on ENaC activity.

scholarly journals Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
Author(s):  
Yanling Yan ◽  
Jiayan Wang ◽  
Muhammad A. Chaudhry ◽  
Ying Nie ◽  
Shuyan Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Significant Rise ◽  
Protein Carbonylation ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells

2002 ◽  
Vol 283 (5) ◽  
pp. F1132-F1141 ◽  
Author(s):  
Violeta Alvarez ◽  
Yasmir Quiroz ◽  
Mayerly Nava ◽  
Héctor Pons ◽  
Bernardo Rodríguez-Iturbe
Keyword(s):  
Interstitial Nephritis ◽  
Renal Damage ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Malondialdehyde Content ◽  
Induced Hypertension ◽  
Salt Sensitive Hypertension ◽  
And Control ◽  
And Oxidative Stress

Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 ± 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg · kg−1 · day−1) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 ± 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.

Effects of a chronic high-salt diet on large artery structure: role of endogenous bradykinin

1998 ◽  
Vol 274 (5) ◽  
pp. H1423-H1428 ◽  
Author(s):  
Chohreh Partovian ◽  
Athanase Benetos ◽  
Jean-Pierre Pommiès ◽  
Willy Mischler ◽  
Michel E. Safar
Keyword(s):  
Blood Pressure ◽  
High Salt ◽  
Large Artery ◽  
High Salt Diet ◽  
Salt Diet ◽  
Wky Rats ◽  
Arterial Blood ◽  
Arterial Structure ◽  
Hoe 140

Bradykinin activity could explain the blood pressure increase during NaCl loading in hypertensive animals, but its contribution on vascular structure was not evaluated. We determined cardiac mass and large artery structure after a chronic, 4-mo, high-salt diet in combination with bradykinin B2-receptor blockade by Hoe-140. Four-week-old rats were divided into eight groups according to strain [spontaneously hypertensive rats (SHR) vs. Wistar-Kyoto (WKY) rats], diet (0.4 vs. 7% NaCl), and treatment (Hoe-140 vs. placebo). In WKY rats, a high-salt diet significantly increased intra-arterial blood pressure with minor changes in arterial structure independently of Hoe-140. In SHR, blood pressure remained stable but 1) the high-salt diet was significantly associated with cardiovascular hypertrophy and increased arterial elastin and collagen, and 2) Hoe-140 alone induced carotid hypertrophy. A high-salt diet plus Hoe-140 acted synergistically on carotid hypertrophy and elastin content in SHR, suggesting that the role of endogenous bradykinin on arterial structure was amplified in the presence of a high-salt diet.

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