scholarly journals Salt-Sensitive Hypertension in GR+/− Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways

2021 ◽  
Vol 22 (24) ◽  
pp. 13218
Author(s):  
Paul-Emmanuel Vanderriele ◽  
Qing Wang ◽  
Anne-Marie Mérillat ◽  
Frédérique Ino ◽  
Gilles Aeschlimann ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epoxide Hydrolase ◽  
Salt Intake ◽  
Soluble Epoxide Hydrolase ◽  
High Salt ◽  
Standard Diet ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Salt Sensitive Hypertension

Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR+/−) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats. Furthermore, GR+/− rats showed dysregulation of the equilibrated linoleic and arachidonic acid pathways, with a significant increase of less active metabolites such as 8,9-DiHETrE. In Sprague Dawley rats, GR haploinsufficiency induced steroid disturbances, which provoked hypertension only in combination with high salt intake, which was accompanied by disturbances in sEH and fatty acid metabolism. Our results suggest that sEH inhibition could be a potential target to treat hypertension in patients with GR haploinsufficiency.

scholarly journals Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats

2019 ◽  
Vol 317 (6) ◽  
pp. F1623-F1636 ◽  
Author(s):  
Alissa A. Frame ◽  
Franco Puleo ◽  
Kiyoung Kim ◽  
Kathryn R. Walsh ◽  
Elizabeth Faudoa ◽  
...  
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Sympathetic Regulation ◽  
Salt Sensitive Hypertension ◽  
And Oxidative Stress ◽  
Resistant Animal

Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na+-evoked suppression of the Na+-Cl− cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α1- and/or β-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α1- and β-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na+-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α1-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na+-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, β-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na+ intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α1-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.

scholarly journals Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

2008 ◽  
Vol 31 (2) ◽  
pp. 62 ◽  
Author(s):  
Sowndramalingam Sankaralingam ◽  
Kaushik M Desai ◽  
Thomas W Wilson
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
And Oxidative Stress ◽  
Hypotensive Response

Purpose: High salt intake causes hypertension and endothelial dysfunction in young Sprague-Dawley rats. Clofibrate (clof) prevents this salt induced hypertension. We asked whether clof can prevent salt-induced endothelial dysfunction, and if so, its mechanism. We also questioned whether high salt intake can induce endothelial dysfunction without hypertension in older animals. Methods: Young (Y, 5 weeks) and old (O, 53 weeks) male Sprague-Dawley rats were given either vehicle (Con, 20 mM Na2CO3) or 0.9% NaCl (Sal) to drink for three weeks. Some young rats received clof (80 mg/d) in their drinking fluid. After three weeks, we measured mean arterial pressure (MAP), endothelial function, by comparing hypotensive responses to acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent), plasma total nitrite+nitrate levels (PNOx), by the Griess reaction, and aortic superoxide production by lucigenin chemiluminescence. Results: Carotid artery MAP did not change in O. Sal-Y developed hypertension: 133±3 vs. 114±2 mmHg, P < 0.001, which was prevented by clof: 105±2 mmHg. ACh induced a similar dose dependent hypotensive response in Con-O and Sal-O that was inhibited by L-NAME (100mg/kg i.v.). Responses to ACh were blunted in Sal-Y but not in Con-Y. Further, L-NAME inhibited ACh responses only in Con-Y. The response to SNP was similar in all animals. Importantly, the ACh-induced hypotensive response was potentiated in clof+Sal-Y, an effect which was attenuated by blocking calcium-activated potassium channels (KCa) with a combination of apamin (50 ug/kg i.v.) + charybdotoxin (50 ug/kg i.v.), but not by L-NAME. PNOx was reduced in Sal-Y compared to Con-Y (2.09±0.26 vs. 4.8±0.35 µM, P < 0.001), but not in Sal-O. Aortic superoxide production was higher (P < 0.001) in Sal-Y (2388±40 milliunits/mg/min) than Sal-O (1107±159 milliunits/mg/min), but was reduced by clof (1378±64 milliunits/mg/min; P < 0.001). Conclusions: High salt intake increases oxidative stress in young animals, leading to impaired nitric oxide activity and endothelial dysfunction. Clofibrate prevents endothelial dysfunction partly through reduced O2?- formation but mainly via selective activation of KCa channels. Older animals are resistant to both salt induced hypertension and oxidative stress.

scholarly journals Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt–Sensitive Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (5) ◽  
pp. 1461-1469
Author(s):  
Franco Puleo ◽  
Kiyoung Kim ◽  
Alissa A. Frame ◽  
Kathryn R. Walsh ◽  
Mohammed Z. Ferdaus ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Chloride ◽  
Salt Intake ◽  
High Salt ◽  
Sodium Reabsorption ◽  
Sprague Dawley ◽  
Sodium Chloride Cotransporter ◽  
High Salt Intake ◽  
Sympathetic Regulation ◽  
Salt Sensitive Hypertension

Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure. The mechanism(s) by which excessive sympathetic nervous system release of norepinephrine influences renal sodium reabsorption is unclear. However, studies demonstrate that norepinephrine can stimulate the activity of the NCC (sodium chloride cotransporter) and promote the development of SSH (salt-sensitive hypertension). The adrenergic signaling pathways governing NCC activity remain a significant source of controversy with opposing studies suggesting a central role of upstream α 1 - and β-adrenoceptors in the canonical regulatory pathway involving WNKs (with-no-lysine kinases), SPAK (STE20/SPS1-related proline alanine-rich kinase), and OxSR1 (oxidative stress response 1). In our previous study, α 1 -adrenoceptor antagonism in norepinephrine-infused male Sprague-Dawley rats prevented the development of norepinephrine-evoked SSH in part by suppressing NCC activity and expression. In these studies, we used selective adrenoceptor antagonism in male Dahl salt–sensitive rats to test the hypothesis that norepinephrine-mediated activation of the NCC in Dahl SSH occurs via an α 1 -adrenoceptor dependent pathway. A high-salt diet evoked significant increases in NCC activity, expression, and phosphorylation in Dahl salt–sensitive rats that developed SSH. Increases were associated with a dysfunctional WNK1/4 dynamic and a failure to suppress SPAK/OxSR1 activity. α 1 -adrenoceptor antagonism initiated before high-salt intake or following the establishment of SSH attenuated blood pressure in part by suppressing NCC activity, expression, and phosphorylation. Collectively, our findings support the existence of a norepinephrine-activated α 1 -adrenoceptor gated pathway that relies on WNK/SPAK/OxSR1 signaling to regulate NCC activity in SSH.

Abstract 328: High Fructose but not High Glucose Intake Induces Salt-sensitive Hypertension and Enhances NKCC2 Phosphorylation in Normal Rats.

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Emily Henson ◽  
Gustavo Ares ◽  
Mohammed Haque ◽  
Pablo Ortiz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Salt Intake ◽  
High Salt ◽  
Sprague Dawley ◽  
High Fructose Diet ◽  
Fructose Intake ◽  
Sprague Dawley Rats ◽  
High Fructose ◽  
Salt Sensitive Hypertension

Consumption of fructose as a sweetener has increased in the past three decades. A high-fructose diet has been implicated in the epidemic of diabetes, obesity, and hypertension. A third of the US population consumes 20-40% of their caloric intake from added sugars, with half of those calories from fructose. Little is known about the role of high fructose intake in renal salt handling and blood pressure regulation during high salt intake. In genetic models of salt-sensitive hypertension, the Na/K/2Cl cotransporter NKCC2 plays an important role by reabsorbing NaCl in the thick ascending limb (TAL). We hypothesized that 20% fructose in drinking water stimulates NKCC2 and sensitizes normal rats to high salt induced hypertension. Adult Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt diet (4% Na in chow) was started. Systolic blood pressure (SBP) was measured every other day by tail cuff after 2 weeks of training. After one week of fructose or glucose alone, SBP did not change. In rats fed fructose, adding a 4% NaCl diet increased SBP to 128±6 mmHg by day 2 (p<0.01 vs glucose) and continued to increase up to 144±18 mmHg after 2 weeks on high salt (p<0.01 vs baseline; p<0.01 vs glucose). In glucose-fed rats high salt did not increase SBP (from 122±6 to 116±9 mmHg). 20% fructose alone for 3 weeks, or high salt alone did not change SBP. NKCC2 phosphorylation at Thr96,101 is associated with enhanced TAL NaCl reabsorption. We found that NKCC2 phosphorylation at Thr96,101 (normalized to total NKCC2) was higher in TALs isolated from rats fed fructose plus salt for 2 weeks compared to high salt alone (high-salt: 100%; fructose + high-salt: 250±40%, p<0.05). We concluded that a high fructose but not high glucose diet induces salt-sensitive hypertension in Sprague Dawley rats. This effect occurs within 1 week of a high fructose diet. In addition, a high fructose diet may stimulate NKCC2 activity by enhancing its phosphorylation. These data suggest that high fructose intake may increase blood pressure by preventing appropriate renal NaCl excretion during high dietary salt intake.

Abstract 142: A Fructose-but Not a Glucose-enriched Diet, Induces a Salt-dependent Increase in Blood Pressure and Enhances NKCC2 Phosphorylation in Normal Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Keyona N King-Medina ◽  
Emily Henson ◽  
Pablo Ortiz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Salt Intake ◽  
Caloric Intake ◽  
High Salt ◽  
Human Consumption ◽  
Thick Ascending Limb ◽  
Sprague Dawley ◽  
High Fructose ◽  
High Salt Intake

Human consumption of fructose as a sweetener has increased in the past 30 years. High fructose intake has been implicated in the development of hypertension, diabetes, and obesity. In the US, the upper 10th percentile of the population consumes up to 40% of their caloric intake from added sugars, in which fructose represents half of these. Fructose metabolism is strikingly different from that of glucose. Yet, the effect of a fructose or glucose-enriched diet in salt handling by the kidney, affecting blood pressure, and its interaction with high salt intake has been poorly studied. In genetic models of salt-sensitive hypertension, the activity of the Na + /K + /2Cl - cotransporter (NKCC2) in the thick ascending limb (TAL) is abnormally enhanced. We hypothesized that chronic fructose in drinking water induces a salt-dependent increase in blood pressure and stimulates NKCC2 during high salt intake in normal rats. Sprague-Dawley rats were given 20% fructose or 20% glucose in drinking water for 1 week after which a high salt (HS) diet (4% Na + in chow) was started for 3 weeks. When we measured systolic blood pressure (SBP) by tail cuff plethysmography in fructose-fed and glucose-fed rats on a HS diet, only the fructose-fed rats had an increased SBP from 120±10 to 132±6 mmHg on day 7 of HS (p<0.01). SBP continued to increase up to 144±18 mmHg after 3 weeks (p<0.01 vs glucose). Fructose or glucose alone did not increase SBP after 4 weeks. We then repeated the protocol using radiotelemetry to monitor the blood pressure (BP). In rats fed fructose, by day 5 of HS the SBP increased by 12±3 mmHg (p<0.02) and SBP remained elevated for 3 weeks (delta: 10±2.5 mmHg, n=3). In rats fed glucose, a HS diet did not significantly change SBP for 3 weeks (n=5). Moreover, NKCC2 activity in the TAL is enhanced by phosphorylation at Thr96, 101. We found that NKCC2 phosphorylation was higher in rats fed fructose plus HS (p<0.02) but not in rats fed glucose plus HS for 3 weeks (HS: 100, fructose+HS: 250±40%, glucose+HS: 95±10%). Therefore, we conclude that a high fructose (but not a glucose) diet in normal rats induces a salt-dependent increase in BP independently from caloric intake. Thus, the increase in BP may in part be due to the stimulation of NKCC2 phosphorylation in the TAL by fructose.

scholarly journals High-Salt Attenuates the Efficacy of Dapagliflozin in Tubular Protection by Impairing Fatty Acid Metabolism in Diabetic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Meina Zou ◽  
Yanrong Chen ◽  
Zongji Zheng ◽  
Shuyue Sheng ◽  
Yijie Jia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Salt Intake ◽  
High Salt ◽  
Renal Tubules ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Renal Tubular

High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD.

Abstract P201: Enhanced Upregulation of (Pro)renin Receptor Expression by High Salt Intake in the Kidney of Dahl Salt-sensitive Rats

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Seiko Yamakoshi ◽  
Osamu Ito ◽  
Rong Rong ◽  
Yusuke Ohsaki ◽  
Yoshikazu Muroya ◽  
...  
Keyword(s):  
Salt Intake ◽  
Immunohistochemical Analysis ◽  
High Salt ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Independent Manner ◽  
Nephron Segments ◽  
High Salt Intake ◽  
Distal Tubules

We recently reported that high salt (HS) intake increased the (pro)renin receptor ((P)RR) expression by 3-5 fold in several nephron segments of Sprague-Dawley rats (Peptides 63: 156-162, 2015). The preset study examined the effects of HS intake on the renal (P)RR expression in Dahl-Salt sensitive (DS) rats. Male DS rats were fed a normal salt (NS) diet (0.6%NaCl) and a HS diet (8%NaCl) for 4weeks. A part of the rats fed the HS diet were treated orally with angiotensin II type 1 receptor (AT 1 R) antagonist, candesartan (Can,3mg/kg/day) or mineralocorticoid receptor (MR) antagonist, spironolactone (Spi, 100mg/kg/day). The (P)RR expression in nephron segments was examined by immunoblot and immunohistochemical analyses. HS intake increased the blood pressure, which did not significantly affected by Can or Spi. (P)RR was expressed in the all kidney sections, glomeruli, proximal tubules (PT), medullary thick ascending limbs and inner medullary collecting ducts. HS intake increased the (P)RR expression in the cortex by 22.6 fold (p<0.001) and the PT by 4.9 fold (p<0.01), but did not change it in the other sections or segments. Can inhibited the HS intake-increased (P)RR expression in the cortex by 32% (p<0.05), Spi inhibited it by 89% (p<0.001), but neither drug did not inhibit the HS intake-increased (P)RR expression in the PT. Immunohistochemical analysis also revealed that HS intake increased the (P)RR expression in the PT and distal tubules, and that Can and Spi inhibited the HS intake-increased (P)RR expression in the distal tubules. Additionally, deoxycorticosterone acetate (DOCA, 50mg/kg/week) administered to rats fed the NS diet for 4 weeks increased the (P)RR expression in the cortex by 80% (p<0.001) and distal tubules, but not in the PT. These results indicate that HS intake-increased (P)RR expression is enhanced in the PT and distal tubules of DS rats. The mechanisms of HS intake-increased (P)RR expression may be AT 1 R and MR-dependent manner in the distal tubules, but AT 1 R or MR-independent manner in the PT.

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