scholarly journals Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF)

2017 ◽  
Vol 313 (6) ◽  
pp. F1209-F1215 ◽  
Author(s):  
Hong Wang ◽  
Cesar A. Romero ◽  
J. X. Masjoan Juncos ◽  
Sumit R. Monu ◽  
Edward L. Peterson ◽  
...  
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Tubuloglomerular Feedback ◽  
Connecting Tubule ◽  
High Salt Intake ◽  
Simultaneous Inhibition ◽  
Flow Pressure ◽  
Tubular Flow

Afferent arteriole (Af-Art) resistance is modulated by two intrinsic nephron feedbacks: 1) the vasoconstrictor tubuloglomerular feedback (TGF) mediated by Na+-K+-2Cl− cotransporters (NKCC2) in the macula densa and blocked by furosemide and 2) the vasodilator connecting tubule glomerular feedback (CTGF), mediated by epithelial Na+ channels (ENaC) in the connecting tubule and blocked by benzamil. High salt intake reduces Af-Art vasoconstrictor ability in Dahl salt-sensitive rats (Dahl SS). Previously, we measured CTGF indirectly, by differences between TGF responses with and without CTGF inhibition. We recently developed a new method to measure CTGF more directly by simultaneously inhibiting NKCC2 and the Na+/H+ exchanger (NHE). We hypothesize that in vivo during simultaneous inhibition of NKCC2 and NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (PSF) in Dahl SS and that is enhanced with a high salt intake. In the presence of furosemide alone, increasing nephron perfusion did not change the PSF in either Dahl salt-resistant rats (Dahl SR) or Dahl SS. When furosemide and an NHE inhibitor, dimethylamiloride, were perfused simultaneously, an increase in tubular flow caused Af-Art dilatation that was demonstrated by an increase in PSF. This increase was greater in Dahl SS [4.5 ± 0.4 (SE) mmHg] than in Dahl SR (2.5 ± 0.3 mmHg; P < 0.01). We confirmed that CTGF causes this vasodilation, since benzamil completely blocked this effect. However, a high salt intake did not augment the Af-Art dilatation. We conclude that during simultaneous inhibition of NKCC2 and NHE in the nephron, CTGF induces Af-Art dilatation and a high salt intake failed to enhance this effect.

Abstract P325: Enhanced Afferent Arteriole Dilatation in Dahl Salt-sensitive Rats (dahlss): Role of Connecting Tubule Glomerular Feedback (ctgf)

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hong Wang ◽  
Cesar A Romero ◽  
Branislava Janic ◽  
Edwards Peterson ◽  
Oscar A Carretero
Keyword(s):  
Indirect Measurement ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
High Salt Diet ◽  
Connecting Tubule ◽  
Simultaneous Inhibition ◽  
Flow Pressure ◽  
Tubular Flow

Afferent arteriole (Af-Art) resistance is modulated by 2 intrinsic nephron feedbacks: the vasoconstrictor tubuloglomerular feedback (TGF) and the vasodilator CTGF. TGF is mediated by NKCC2 channel in the macula densa and blocked by furosemide; and CTGF is mediated by ENaC in the connecting tubule and blocked by benzamil. Previously we measured CTGF indirectly, by differences between TGF response with and without CTGF blocker benzamil. Thus, using this indirect measurement we reported that Dahl SS have greater CTGF than Dahl salt-resistant rats (Dahl SR). We have recently developed a new method to measure CTGF more directly and we found that when we simultaneously blocked TGF with furosemide and CTGF with benzamil, the increasing tubular perfusion caused Af-Art constriction (TGF-like) that is mediated by the NHE. W e hypothesize that in vivo during simultaneous inhibition of NKCC2 and the NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (P SF ) and that is greater in Dahl SS than in Dahl SR in a high salt diet. In the presence of furosemide alone, increasing nephron perfusion did not change the P SF in neither Dahl SS nor Dahl SR. When we blocked both, NKCC2 with furosemide and NHE with DMA, increase in tubular flow caused Af-Art dilation that was demonstrated by an increase in P SF . This increase was greater in Dahl SS (5.1±0.4 mmHg) than in Dahl SR (2.9±0.3 mmHg; P < 0.01), (Fig).We confirm that CTGF causes this vasodilation, since benzamil completely blocked this effect. We conclude that during inhibition of NKCC2 and NHE in the nephron CTGF (Af-Art dilatation) is enhanced in Dahl SS as compared to Dahl SR.

Abstract 062: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Connecting Tubule Glomerular Feedback

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sumit R Monu ◽  
Mani Maheshwari ◽  
Hong Wang ◽  
Ed Peterson ◽  
Oscar Carretero
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Connecting Tubule ◽  
Single Nephron ◽  
Renal Micropuncture ◽  
The Difference

In obesity, renal damage is caused by increase in renal blood flow (RBF), glomerular capillary pressure (P GC ), and single nephron glomerular filtration rate but the mechanism behind this alteration in renal hemodynamics is unclear. P GC is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance is regulated by mechanism similar to that in other arterioles and in addition, it is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa, via sodium–potassium-2-chloride cotransporter-2 (NKCC2) and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation and is mediated by connecting tubule via epithelial sodium channel (ENaC). CTGF is blocked by the ENaC inhibitor benzamil. Attenuation of TGF reduces Af-Art resistance and allows systemic pressure to get transmitted to the glomerulus that causes glomerular barotrauma/damage. In the current study, we tested the hypothesis that TGF is attenuated in obesity and that CTGF contributes to this effect. We used Zucker obese rats (ZOR) while Zucker lean rats (ZLR) served as controls. We performed in-vivo renal micropuncture of individual rat nephrons while measuring stop-flow pressure (P SF ), an index of P GC. TGF response was measured as a decrease in P SF induced by changing the rate of late proximal perfusion from 0 to 40nl/min in stepwise manner.CTGF was calculated as the difference of P SF value between vehicle and benzamil treatment, at each perfusion rate. Maximal TGF response was significantly less in ZOR (6.16 ± 0.52 mmHg) when compared to the ZLR (8.35 ± 1.00mmHg), p<0.05 , indicating TGF resetting in the ZOR. CTGF was significantly higher in ZOR (6.33±1.95 mmHg) when compared to ZLR (1.38±0.89 mmHg), p<0.05 . When CTGF was inhibited with the ENaC blocker Benzamil (1μM), maximum P SF decrease was 12.30±1.72 mmHg in ZOR and 10.60 ± 1.73 mmHg in ZLR, indicating that blockade of CTGF restored TGF response in ZOR. These observations led us to conclude that TGF is reset in ZOR and that enhanced CTGF contributes to this effect. Increase in CTGF may explain higher renal blood flow, increased P GC and higher glomerular damage in obesity.

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.

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 High Salt Intake Augments Excitability of PVN Neurons in Rats: Role of the Endoplasmic Reticulum Ca2+ Store

2017 ◽  
Vol 11 ◽  
Author(s):  
Robert A. Larson ◽  
Andrew D. Chapp ◽  
Le Gui ◽  
Michael J. Huber ◽  
Zixi Jack Cheng ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Salt Intake ◽  
High Salt ◽  
High Salt Intake

scholarly journals High-salt intake enhances superoxide activity in eNOS knockout mice leading to the development of salt sensitivity

2010 ◽  
Vol 299 (3) ◽  
pp. F656-F663 ◽  
Author(s):  
Libor Kopkan ◽  
Arthur Hess ◽  
Zuzana Husková ◽  
Luděk Červenka ◽  
L. Gabriel Navar ◽  
...  
Keyword(s):  
Salt Intake ◽  
Salt Sensitivity ◽  
High Salt ◽  
No Production ◽  
Wild Type ◽  
Total N ◽  
High Salt Intake ◽  
Excretion Rates ◽  
Salt Sensitive Hypertension

A deficiency in nitric oxide (NO) generation leads to salt-sensitive hypertension, but the role of increased superoxide (O2−) in such salt sensitivity has not been delineated. We examined the hypothesis that an enhancement in O2− activity induced by high-salt (HS) intake under deficient NO production contributes to the development of salt-sensitive hypertension. Endothelial NO synthase knockout (eNOS KO; total n = 64) and wild-type (WT; total n = 58) mice were given diets containing either normal (NS; 0.4%) or high-salt (HS; 4%) for 2 wk. During this period, mice were chronically treated with a O2− scavenger, tempol (400 mg/l), or an inhibitor of NADPH oxidase, apocynin (1 g/l), in drinking water or left untreated ( n = 6–8 per group). Blood pressure was measured by radiotelemetry and 24-h urine samples were collected in metabolic cages. Basal mean arterial pressure (MAP) in eNOS KO was higher (125 ± 4 vs. 106 ± 3 mmHg) compared with WT. Feeding HS diet did not alter MAP in WT but increased it in eNOS KO to 166 ± 9 mmHg. Both tempol and apocynin treatment significantly attenuated the MAP response to HS in eNOS KO (134 ± 3 and 139 ± 4 mmHg, respectively). Basal urinary 8-isoprostane excretion rates (UIsoV), a marker for endogenous O2− activity, were similar (2.8 ± 0.2 and 2.4 ± 0.3 ng/day) in both eNOS KO and WT mice. However, HS increased UIsoV more in eNOS KO than in WT (4.6 ± 0.3 vs. 3.8 ± 0.2 ng/day); these were significantly attenuated by both tempol and apocynin treatment. These data indicate that an enhancement in O2− activity contributes substantially to the development of salt-sensitive hypertension under NO-deficient conditions.

scholarly journals High Salt Intake Increases Blood Pressure in Normal Rats: Putative Role of 20-HETE and No Evidence on Changes in Renal Vascular Reactivity

2015 ◽  
Vol 40 (3) ◽  
pp. 323-334 ◽  
Author(s):  
A. Walkowska ◽  
M. Kuczeriszka ◽  
J. Sadowski ◽  
K.H. Olszyñski ◽  
L. Dobrowolski ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Reactivity ◽  
Salt Intake ◽  
High Salt ◽  
Putative Role ◽  
High Salt Intake ◽  
Renal Vascular
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