scholarly journals High Salt Intake–Increased (Pro)renin Receptor Expression Is Exaggerated in the Kidney of Dahl Salt-Sensitive Rats

Hypertension ◽  
2020 ◽  
Vol 75 (6) ◽  
pp. 1447-1454
Author(s):  
Seiko Yamakoshi ◽  
Osamu Ito ◽  
Rong Rong ◽  
Yusuke Ohsaki ◽  
Takahiro Nakamura ◽  
...  
Keyword(s):  
Renal Cortex ◽  
Salt Intake ◽  
High Salt ◽  
Proximal Tubules ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Mineralocorticoid Receptor Antagonist ◽  
Salt Diet ◽  
High Salt Intake ◽  
Distal Tubules

The (P)RR ([pro]renin receptor) was identified as a new component of the renin-angiotensin system. We previously reported that high salt (HS) intake increased the (P)RR expression in several nephron segments of Sprague-Dawley rats. Other studies reported HS intake increased the XO (xanthine oxidase) activity and an MR (mineralocorticoid receptor) antagonist inhibited HS intake–increased (P)RR expression in the kidneys of Dahl salt-sensitive (DS) rats. The present study examined the effects of HS intake on (P)RR expression in the kidney of DS rats. Male DS rats were fed a normal salt diet or an HS diet for 4 weeks. Some of the rats fed on the HS diet were treated with the XO inhibitor, febuxostat, and the MR antagonist, spironolactone. Immunoblot and immunohistochemical analyses showed that HS intake increased (P)RR expression in the renal cortex by 22.6-fold, the proximal tubules by 4.9-fold and the distal tubules, respectively. Both febuxostat and spironolactone inhibited HS intake–increased (P)RR expression in the renal cortex. Febuxostat inhibited HS intake–increased (P)RR expression in the proximal tubules, whereas spironolactone inhibited HS intake–increased (P)RR expression in the distal tubules. Additionally, deoxycorticosterone acetate increased (P)RR expression in the renal cortex and distal tubules but not in the proximal tubules of DS rats fed the normal salt diet. These results indicate that HS intake greatly increases (P)RR expression in the renal cortex of DS rats. The mechanisms of HS intake–increased (P)RR expression may work in an XO-dependent manner in the proximal tubules and an MR-dependent manner in the distal tubules.

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.

scholarly journals Eplerenone inhibits aldosterone-induced renal expression of cyclooxygenase

2012 ◽  
Vol 13 (3) ◽  
pp. 353-359 ◽  
Author(s):  
MA Bayorh ◽  
A Rollins-Hairston ◽  
J Adiyiah ◽  
D Lyn ◽  
D Eatman
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Prostaglandin E ◽  
Renal Tubules ◽  
Protective Effects ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Cox 2

Introduction: The upregulation of cyclooxygenase (COX) expression by aldosterone (ALDO) or high salt diet intake is very interesting and complex in the light of what is known about the role of COX in renal function. Thus, in this study, we hypothesize that apocynin (APC) and/or eplerenone (EPL) inhibit ALDO/salt-induced kidney damage by preventing the production of prostaglandin E2 (PGE2). Methods: Dahl salt-sensitive rats on either a low-salt or high-salt diet were treated with ALDO (0.2 mg pellet) in the presence of EPL (100 mg/kg/day) or APC (1.5 mM). Indirect blood pressure, prostaglandins and ALDO levels and histological changes were measured. Results: Cyclooxygenase-2 (COX-2) levels were upregulated in the renal tubules and peritubular vessels after high-salt intake, and APC attenuated renal tubular COX-2 protein expression induced by ALDO. Plasma PGE2 levels were significantly reduced by ALDO in the rats fed a low-salt diet when compared to rats fed a high-salt diet. PGE2 was blocked by EPL but increased in the presence of APC. Conclusions: The beneficial effects of EPL may be associated with an inhibition of PGE2. The mechanism underlying the protective effects of EPL is clearly distinct from that of APC and suggests that these agents can have differential roles in cardiovascular disease.

Abstract 138: High Salt Intake Augments Excitability of Pre-sympathetic PVN Neurons Through Dysfunction of the Endoplasmic Reticulum Ca2+ ATPase

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Robert A Larson ◽  
Andrew D Chapp ◽  
Michael J Huber ◽  
Zixi Cheng ◽  
Zhiying Shan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Salt Intake ◽  
Sympathetic Neurons ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Atpase Inhibitor ◽  
High Salt Intake ◽  
Significant Difference

High salt (HS) intake sensitizes pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) leading to augmented neuronal excitability. Recently, we reported that dysfunction of Ca 2+ dependent K + channels in the PVN contributes to HS intake induced sympathoexcitation. The endoplasmic reticulum (ER) acts as a Ca 2+ store and plays an important role in regulating intracellular Ca 2+ homeostasis. The ER Ca 2+ ATPase is responsible for maintaining the high level of ER Ca 2+ and loss of function would deplete the Ca 2+ store contributing to the reduced activity of Ca 2+ dependent K + channels. We hypothesized that a 2% (NaCl) HS diet for 5 weeks would reduce function of the ER Ca 2+ ATPase and augment excitability of PVN neurons with axon projections to the rostral ventrolateral medulla (PVN-RVLM) identified by retrograde label. In whole cell current-clamp recordings from PVN-RVLM neurons, graded current injections evoked graded increases in spike frequency. Maximum discharge was evoked by +200 pA injections and averaged 22±2 Hz (n=6) in normal salt (NS) control and was significantly augmented (p<0.05) by HS diet 34±5 Hz (n=8). Bath application of thapsigargin (TG) (0.5 μM), the ER Ca 2+ ATPase inhibitor, augmented excitability of PVN-RVLM neurons in NS (32±4 Hz, n=5, p<0.05), yet had no significant effect in HS rats (32±6 Hz, n=6). ER Ca 2+ ATPase function was assessed in whole animal preparations by bilateral PVN microinjection of TG in anesthetized rats. PVN microinjection of TG (0.15, 0.3 0.75 and 1.5 nmol/100nl) increased sympathetic nerve activity (SNA) and mean arterial pressure (MAP) in a dose-dependent manner in NS rats. Maximum increases in splanchnic SNA (SSNA), renal SNA (RSNA) and MAP elicited by PVN TG (0.75 nmol/100nl; n=5) were 93±7%, 75±7%, and 11±2mmHg, respectively. In contrast, sympathoexcitatory responses to PVN TG (0.75 nmol/100nl; n=5) were attenuated in HS treated rats (SSNA 41±8%, RSNA 22±5%, p<0.05 vs. NS) while MAP responses demonstrated no significant difference (+8±2 mmHg, p>0.05 vs NS). Our data indicate that a HS diet reduces ER Ca 2+ ATPase activity and augments excitability of PVN-RVLM neurons in vitro. Altered ER Ca 2+ homeostasis may contribute to sympathoexcitation through loss of Ca 2+ dependent K + channel activity in the PVN.

scholarly journals SAT-119 Mechanisms of (Pro)renin Receptor Expression in the Kidney of Dahl Salt-Sensitive Rats by High Salt Intake

2019 ◽  
Vol 4 (7) ◽  
pp. S55
Author(s):  
S. YAMAKOSHI ◽  
O. Ito ◽  
Y. Osaki ◽  
T. Nakamura ◽  
T. Kazuhiro ◽  
...  
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Receptor Expression ◽  
High Salt Intake

scholarly journals Salt-sensitive splice variant of nNOS expressed in the macula densa cells

2010 ◽  
Vol 298 (6) ◽  
pp. F1465-F1471 ◽  
Author(s):  
Deyin Lu ◽  
Yiling Fu ◽  
Arnaldo Lopez-Ruiz ◽  
Rui Zhang ◽  
Ramiro Juncos ◽  
...  
Keyword(s):  
Salt Intake ◽  
Splice Variants ◽  
Macula Densa ◽  
High Salt ◽  
Tubuloglomerular Feedback ◽  
No Production ◽  
Thick Ascending Limb ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake

Neuronal nitric oxide synthase (nNOS), which is abundantly expressed in the macula densa cells, attenuates tubuloglomerular feedback (TGF). We hypothesize that splice variants of nNOS are expressed in the macula densa, and nNOS-β is a salt-sensitive isoform that modulates TGF. Sprague-Dawley rats received a low-, normal-, or high-salt diet for 10 days and levels of the nNOS-α, nNOS-β, and nNOS-γ were measured in the macula densa cells isolated with laser capture microdissection. Three splice variants of nNOS, α-, β-, and γ-mRNAs, were detected in the macula densa cells. After 10 days of high-salt intake, nNOS-α decreased markedly, whereas nNOS-β increased two- to threefold in the macula densa measured with real-time PCR and in the renal cortex measured with Western blot. NO production in the macula densa was measured in the perfused thick ascending limb with an intact macula densa plaque with a fluorescent dye DAF-FM. When the tubular perfusate was switched from 10 to 80 mM NaCl, a maneuver to induce TGF, NO production by the macula densa was increased by 38 ± 3% in normal-salt rats and 52 ± 6% ( P < 0.05) in the high-salt group. We found 1) macula densa cells express nNOS-α, nNOS-β, and nNOS-γ, 2) a high-salt diet enhances nNOS-β, and 3) TGF-induced NO generation from macula densa is enhanced in high-salt diet possibly from nNOS-β. In conclusion, we found that the splice variants of nNOS expressed in macula densa cells were α-, β-, and γ-isoforms and propose that enhanced level of nNOS-β during high-salt intake may contribute to macula densa NO production and help attenuate TGF.

Altered peripheral noradrenergic activity in intact and sinoaortic denervated Dahl rats

1989 ◽  
Vol 67 (5) ◽  
pp. 442-449 ◽  
Author(s):  
J. D. Peuler ◽  
K. P. Patel ◽  
D. A. Morgan ◽  
C. A. Whiteis ◽  
D. D. Lund ◽  
...  
Keyword(s):  
Sympathetic Activity ◽  
Sinoatrial Node ◽  
Renal Cortex ◽  
Salt Intake ◽  
Left Ventricular ◽  
High Salt ◽  
Arterial Baroreflex ◽  
High Salt Intake ◽  
Cardiac Ventricle ◽  
Cardiac Ventricles

Development of salt-induced hypertension in Dahl salt-sensitive (S) rats is dependent on sympathetic overactivity which may be partially related to arterial baroreflex dysfunction and, therefore, is regionally selective. Our first experiment was designed to determine which regions have elevated sympathetic activity in Dahl S compared with Dahl salt-resistant (R) rats. Weanling (4-week-old) female Dahl R and S rats were fed low or high salt diets (0.13% and 8% NaCl) until 10 weeks of age. Norepinephrine (NE) synthesis was blocked with α-methyl-p-tyrosine, and the fractional decline of NE concentration was measured in various tissues. Dahl S rats with increases in both arterial pressure and left ventricular weight demonstrated increased NE turnover in the sinoatrial node, the atrial appendages, the cardiac ventricles, and the renal cortex. In all of these tissues except the cardiac ventricle, increases were associated with high salt intake. Our second experiment was designed to test if arterial baroreflex dysfunction could account for regional increases in sympathetic activity. Separate groups of Dahl R and S rats fed high salt were subjected to either sham surgery or sinoaortic baroreceptor denervation 1 week prior to turnover determinations. Sinoaortic baroreceptor denervation abolished differences in NE turnover between salt-fed Dahl R and S rats in the cardiac sinoatrial node and the atrial appendages, but not in the cardiac ventricles and the renal cortex. Sinoaortic baroreceptor denervation also abolished differences between salt-fed Dahl S and R rats in the spleen but not the duodenum. Thus in awake, undisturbed Dahl S rats, sympathetic activity may be increased in the cardiac ventricles, regardless of salt intake. High salt intake may induce elevated sympathetic activity in the renal cortex and in the cardiac atria and sinoatrial node of Dahl S but not R rats. Sinoaortic baroreflex dysfunction in Dahl S rats may contribute to some, but not all, regional increases in sympathetic activity.Key words: high salt intake, hypertension, cardiac hypertrophy, norepinephrine turnover, sympathetic activity, sinoaortic denervation.

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.

Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation

2015 ◽  
Vol 308 (5) ◽  
pp. H530-H539 ◽  
Author(s):  
Koji Ito ◽  
Yoshitaka Hirooka ◽  
Kenji Sunagawa
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Salt Intake ◽  
Receptor Activation ◽  
High Salt ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake ◽  
Tnf Α ◽  
Excitatory Responses

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na+ channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na+, we performed an intracerebroventricular infusion of high Na+-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.

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.

Regulation ofP-450 4A activity in the glomerulus of the rat

1999 ◽  
Vol 276 (6) ◽  
pp. R1749-R1757 ◽  
Author(s):  
Osamu Ito ◽  
Richard J. Roman
Keyword(s):  
Arachidonic Acid ◽  
Salt Intake ◽  
High Salt ◽  
Dependent Manner ◽  
Hydroxyeicosatetraenoic Acid ◽  
Dietary Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Dietary Salt Intake ◽  
Low Salt

We recently reported that an enzyme of the cytochrome P-450 4A family is expressed in the glomerulus, but there is no evidence that 20-hydroxyeicosatetraenoic acid (20-HETE) can be produced by this tissue. The purpose of present study was to determine whether glomeruli isolated from the kidney of rats can produce 20-HETE and whether the production of this metabolite is regulated by nitric oxide (NO) and dietary salt intake. Isolated glomeruli produced 20-HETE, dihydroxyeicosatrienoic acids, and 12-hydroxyeicosatetraenoic acid (4.13 ± 0.38, 4.20 ± 0.38, and 2.10 ± 0.20 pmol ⋅ min−1⋅ mg protein−1, respectively) when incubated with arachidonic acid (10 μM). The formation of 20-HETE was dependent on the availability of NADPH and the[Formula: see text] of the incubation medium. The formation of 20-HETE was inhibited by NO donors in a concentration-dependent manner. The production of 20-HETE was greater in glomeruli isolated from the kidneys of rats fed a low-salt diet than in kidneys of rats fed a high-salt diet (5.67 ± 0.32 vs. 2.83 ± 0.32 pmol ⋅ min−1⋅ mg protein−1). Immunoblot experiments indicated that the expression of P-450 4A protein in glomeruli from the kidneys of rats fed a low-salt diet was sixfold higher than in kidneys of rats fed a high-salt diet. These results indicate that arachidonic acid is primarily metabolized to 20-HETE and dihydroxyeicosatrienoic acids in glomeruli and that glomerular P-450 activity is modulated by NO and dietary salt intake.

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