Febuxostat ameliorates high salt intake-induced hypertension and renal damage in Dahl salt-sensitive rats

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Takahiro Miura ◽  
Akihiro Sakuyama ◽  
Lusi Xu ◽  
Jiahe Qiu ◽  
Asako Namai-Takahashi ◽  
...  
Keyword(s):  
Renal Damage ◽  
Salt Intake ◽  
High Salt ◽  
High Salt Intake ◽  
Induced Hypertension

scholarly journals Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage

2013 ◽  
Vol 304 (6) ◽  
pp. R407-R414 ◽  
Author(s):  
David L. Mattson ◽  
Hayley Lund ◽  
Chuanling Guo ◽  
Nathan Rudemiller ◽  
Aron M. Geurts ◽  
...  
Keyword(s):  
Immune Cells ◽  
Renal Damage ◽  
Salt Intake ◽  
Disease Process ◽  
Genetic Mutation ◽  
High Salt ◽  
Tubular Damage ◽  
Arterial Blood ◽  
High Salt Intake ◽  
Recombination Activating Gene

Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc finger nuclease targeting bases 672–706 of recombination-activating gene 1 (Rag1) was injected into the pronucleus of Dahl SS (SS/JrHsdMcwi) strain embryos and implanted in pseudopregnant females. This strategy yielded a rat strain with a 13-base frame-shift mutation in the target region of Rag1 and a deletion of immunoreactive Rag1 protein in the thymus. Flow cytometry demonstrated that the Rag1-null mutant rats have a significant reduction in T and B lymphocytes in the circulation and spleen. Studies were performed on SS and Rag1-null rats fed a 4.0% NaCl diet for 3 wk. The infiltration of T cells into the kidney following high-salt intake was significantly blunted in the Rag1-null rats (1.7 ± 0.6 × 105 cells/kidney) compared with the Dahl SS (5.6 ± 0.9 × 105 cells/kidney). Accompanying the reduction in infiltration of immune cells in the kidney, mean arterial blood pressure and urinary albumin excretion rate were significantly lower in Rag1-null mutants (158 ± 3 mmHg and 60 ± 16 mg/day, respectively) than in SS rats (180 ± 11 mmHg and 251 ± 37 mg/day). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the SS rats fed a high-salt diet was also attenuated in the Rag1 mutants. These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats.

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.

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 Conditional knockout of collecting duct bradykinin B2 receptors exacerbates angiotensin II-induced hypertension during high salt intake

2015 ◽  
Vol 38 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Libor Kopkan ◽  
Zuzana Husková ◽  
Šárka Jíchová ◽  
Lenka Červenková ◽  
Luděk Červenka ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Salt Intake ◽  
Collecting Duct ◽  
High Salt ◽  
Conditional Knockout ◽  
High Salt Intake ◽  
Induced Hypertension ◽  
B2 Receptors

Effect of dietary salt on arteriolar nitric oxide in striated muscle of normotensive rats

1993 ◽  
Vol 264 (6) ◽  
pp. H1810-H1816 ◽  
Author(s):  
M. A. Boegehold
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Striated Muscle ◽  
Salt Intake ◽  
High Salt ◽  
Dietary Salt ◽  
Dietary Salt Intake ◽  
High Salt Intake ◽  
Low Salt ◽  
Induced Hypertension

This study evaluated the influence of high dietary salt intake on nitric oxide (NO) activity in the arteriolar network of rats resistant to salt-induced hypertension. The spinotrapezius muscle microvasculature was studied in inbred Dahl salt-resistant (SR/Jr) rats fed low (0.45%)- or high (7%)-salt diets for 4–5 wk. Arterial pressures were not different between groups at any time during the study. NO synthesis inhibition with NG-nitro-L-arginine-methyl ester (L-NAME) constricted arcade arterioles in low-salt SR/Jr and dilated arcade arterioles in high-salt SR/Jr. Arcade arteriole dilation to acetylcholine (ACh), but not sodium nitroprusside (SNP), was impaired in high-salt SR/Jr. In contrast, transverse and distal arteriole responses to L-NAME, ACh, and SNP were identical in high- and low-salt SR/Jr. These findings indicate that high salt intake, in the absence of increased arterial pressure, suppresses the influence of basal and evoked NO on vascular tone in arcading arterioles, but not in smaller transverse and distal arterioles. Unaltered SNP responses in high-salt SR/Jr suggest that this effect does not involve a change in arteriolar smooth muscle responsiveness to NO.

scholarly journals NOX4/H 2 O 2 /mTORC1 Pathway in Salt-Induced Hypertension and Kidney Injury

Hypertension ◽  
2020 ◽  
Vol 76 (1) ◽  
pp. 133-143 ◽  
Author(s):  
Vikash Kumar ◽  
Theresa Kurth ◽  
Nadezhda N. Zheleznova ◽  
Chun Yang ◽  
Allen W. Cowley
Keyword(s):  
Renal Injury ◽  
Immune Cell ◽  
Salt Intake ◽  
Chronic Phase ◽  
Kidney Injury ◽  
High Salt ◽  
High Salt Intake ◽  
Induced Hypertension

We have reported that a high-salt (4.0% NaCl) dietary intake activates mTORC1 and inhibition of this pathway with rapamycin blunts the chronic phase of salt-induced hypertension and renal injury in Dahl salt-sensitive (SS) rats. In SS rats, high-salt intake is known to increase the renal production of H 2 O 2 by NOX4, the most abundant NOX isoform in the kidney, and the global knockout of NOX4 blunts salt-sensitivity in these rats. Here, we explored the hypothesis that elevations of H 2 O 2 by NOX4 in high-salt fed SS rat stimulate mTORC1 for the full development of salt-induced hypertension and renal injury. Our in vitro studies found that H 2 O 2 activates mTORC1 independent of PI3K/AKT and AMPK pathways. To determine the in vivo relevance of NOX4/H 2 O 2 /mTORC1 in the salt-induced hypertension, SS- Nox4 knockout (SS Nox4 −/− ) rats were daily administrated with vehicle/rapamycin fed a high-salt diet for 21 days. Rapamycin treatment of SS Nox4−/− rats had shown no augmented effect on the salt-induced hypertension nor upon indices of renal injury. Significant reductions of renal T lymphocyte and macrophage together with inhibition of cell proliferation were observed in rapamycin treated rats suggesting a role of mTORC1 independent of NOX4 in the proliferation of immune cell. Given the direct activation of mTORC1 by H 2 O 2 and absence of any further protection from salt-induced hypertension in rapamycin-treated SS Nox4 −/− rats, we conclude that NOX4-H 2 O 2 is a major upstream activator of mTORC1 that contributes importantly to salt-induced hypertension and renal injury in the SS rat model.

Dietary salt decreases cytosolic calcium in platelets from Dahl salt-sensitive rats

1995 ◽  
Vol 269 (5) ◽  
pp. R1225-R1229 ◽  
Author(s):  
T. Ishida ◽  
M. Ishida ◽  
H. Matsuura ◽  
R. Ozono ◽  
G. Kajiyama ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Salt Intake ◽  
Cytosolic Calcium ◽  
High Salt ◽  
Dietary Salt ◽  
Fura 2 ◽  
High Salt Intake ◽  
Induced Hypertension

To determine whether abnormal cellular Ca2+ handling is involved in salt-induced hypertension of Dahl salt-sensitive rats (DS), we investigated Ca2+ handling in fura 2-loaded platelets of DS and Dahl salt-resistant rats (DR) fed a high-NaCl (8%) or a low-NacL (0.3%) diet for 4 wk from 5 wk of age. At 5 wk of age, blood pressure, resting cytosolic Ca2+ concentration ([Ca2+]i), the thrombin-evoked increase in [Ca2+]i and the size of internal Ca2+ stores of DS were comparable with those of DR. After 4 wk on the diets, resting [Ca2+]i of DS on high-NaCl diet was lower than that of DS on low-NaCl diet, and there was no effect of high salt intake on resting [Ca2+]i in DR. In DS, high salt intake attenuated the [Ca2+]i response to thrombin in the presence of external Ca2+. In contrast, the [Ca2+]i response to thrombin in the absence of external Ca2+ was enhanced by high salt intake in DS. The size of internal Ca2+ stores was increased by high salt intake in DS but not in DR. These data suggest that it is not obligatory for hypertension to be accompanied by an increase in platelet [Ca2+]i.

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