Hypotension in NKCC1 null mice: role of the kidneys

2006 ◽  
Vol 290 (2) ◽  
pp. F409-F416 ◽  
Author(s):  
Susan M. Wall ◽  
Mark A. Knepper ◽  
Kathryn A. Hassell ◽  
Michael P. Fischer ◽  
Adetola Shodeinde ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Kidney Tissue ◽  
Free Water ◽  
Plasma Renin ◽  
Wild Type ◽  
Deficient Diet ◽  
Water Excretion ◽  
Α Subunit ◽  
Serum Aldosterone ◽  
Transporter Expression

NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored. Therefore, we asked 1) whether NKCC1 ( −/−) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether the hypotension observed in these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter expression. Thus we performed balance studies, semiquantitative immunoblotting, and immunohistochemistry of kidney tissue from NKCC1 ( +/+) and NKCC1 ( −/−) mice which consumed either a high (2.8% NaCl)- or a low-NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in NKCC1 ( −/−) than NKCC1 ( +/+) mice following either high or low dietary NaCl intake. Relative to wild-type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was either the same or only slightly increased in the mutant mice. Expression of NHE3, the α-subunit of the Na-K-ATPase, NCC, and NKCC2 were higher in NKCC1 null than in wild-type mice, although differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to excrete free water than wild-type mice, which resulted in hypochloremia following the NaCl-deficient diet. Hypochloremia did not occur from increased aquaporin-1 (AQP1) or 2 protein expression or from redistribution of AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary osmolality following vasopressin administration, which should increase free water excretion and attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice, which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin, and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and blood pressure, thus minimizing hypotension.

scholarly journals Salt sensitivity of blood pressure in NKCC1-deficient mice

2008 ◽  
Vol 295 (4) ◽  
pp. F1230-F1238 ◽  
Author(s):  
Soo Mi Kim ◽  
Christoph Eisner ◽  
Robert Faulhaber-Walter ◽  
Diane Mizel ◽  
Susan M. Wall ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Wheel Running ◽  
Plasma Renin ◽  
Pressure Change ◽  
Standard Diet ◽  
Wild Type ◽  
Vascular Effects ◽  
Arterial Blood ◽  
Deficient Mice

NKCC1 is a widely expressed isoform of the Na-2Cl-K cotransporter that mediates several direct and indirect vascular effects and regulates expression and release of renin. In this study, we used NKCC1-deficient (NKCC1−/−) and wild-type (WT) mice to assess day/night differences of blood pressure (BP), locomotor activity, and renin release and to study the effects of high (8%) or low (0.03%) dietary NaCl intake on BP, activity, and the renin/aldosterone system. On a standard diet, 24-h mean arterial blood pressure (MAP) and heart rate determined by radiotelemetry, and their day/night differences, were not different in NKCC1−/− and WT mice. Spontaneous and wheel-running activities in the active night phase were lower in NKCC1−/− than WT mice. In NKCC1−/− mice on a high-NaCl diet, MAP increased by 10 mmHg in the night without changes in heart rate. In contrast, there was no salt-dependent blood pressure change in WT mice. MAP reductions by hydralazine (1 mg/kg) or isoproterenol (10 μg/mouse) were significantly greater in NKCC1−/− than WT mice. Plasma renin (PRC; ng ANG I·ml−1·h−1) and aldosterone (aldo; pg/ml) concentrations were higher in NKCC1−/− than WT mice (PRC: 3,745 ± 377 vs. 1,245 ± 364; aldo: 763 ± 136 vs. 327 ± 98). Hyperreninism and hyperaldosteronism were found in NKCC1−/− mice during both day and night. High Na suppressed PRC and aldosterone in both NKCC1−/− and WT mice, whereas a low-Na diet increased PRC and aldosterone in WT but not NKCC1−/− mice. We conclude that 24-h MAP and MAP circadian rhythms do not differ between NKCC1−/− and WT mice on a standard diet, probably reflecting a balance between anti- and prohypertensive factors, but that blood pressure of NKCC1−/− mice is more sensitive to increases and decreases of Na intake.

Hypertension in Dahl salt-sensitive rats: biochemical and immunohistochemical studies

1992 ◽  
Vol 83 (1) ◽  
pp. 13-22 ◽  
Author(s):  
J. Bouhnik ◽  
J. P. Richoux ◽  
H. Huang ◽  
F. Savoie ◽  
T. Baussant ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Plasma Renin Activity ◽  
Plasma Renin ◽  
High Salt ◽  
Renin Activity ◽  
Deficient Diet ◽  
High Salt Diet ◽  
Salt Diet ◽  
Plasma Angiotensin

1. The renin-angiotensin and kinin-kallikrein systems of Dahl salt-sensitive and salt-resistant rats fed diets with different salt contents were analysed using biochemical and immunocytochemical techniques. 2. Blood pressure increased by 45% in salt-sensitive rats only, after 4 weeks on a high-salt diet. The plasma renin activity and plasma angiotensin II concentration remained at the same levels in salt-sensitive rats on the high-salt diet as on the normal salt diet, whereas the plasma renin activity and plasma angiotensin II concentration of salt-resistant rats fed the high-salt diet were lower. The plasma renin activity and the plasma angiotensin II concentration were elevated in both salt-resistant and salt-sensitive rats fed the salt-deficient diet but were much more elevated in salt-resistant than in salt-sensitive rats. 3. The kidney immunocytochemical data paralleled the data on plasma parameters. Salt-sensitive rats had fewer renin positive juxtaglomerular apparatuses than salt-resistant rats on the normal diet, and the increase on the sodium-deficient diet was also smaller in salt-sensitive rats. Salt-sensitive rats fed the high-salt diet and the standard diet had almost no angiotensin II immunoreactivity compared with the salt-resistant rats on the same diets. 4. The total renal kallikrein content of salt-sensitive rats was lower than that of salt-resistant rats on all three diets, as was the amount of kallikrein excreted in the urine on the standard and the high-salt diets. The differences resulted from a reduction in active kallikrein. The increase in kallikrein in salt-sensitive and salt-resistant rats on the salt-deficient diet was not significantly different. 5. There were similar changes in immunopositive kallikrein in the kidneys of salt-sensitive and salt-resistant rats with diet, with a large increase in kallikrein biosynthesis on the low-salt diet. The plasma concentration of high-molecular-mass kininogen was not significantly different in salt-sensitive and salt-resistant rats, but there was a significant increase in T-kininogen in salt-sensitive rats fed the high-salt diet. 6. In conclusion, the absence of decreases in the plasma renin activity and the plasma angiotensin II concentration in salt-sensitive rats fed the high-salt diet might partially explain the increase in blood pressure.

Intrarenal Distribution of Plasma Flow in Cirrhosis as Measured by Transit Renography: Relationship with Plasma Renin Activity, and Sodium and Water Excretion

1977 ◽  
Vol 52 (5) ◽  
pp. 469-475 ◽  
Author(s):  
S. P. Wilkinson ◽  
I. K. Smith ◽  
M. Clarke ◽  
V. Arroyo ◽  
J. Richardson ◽  
...  
Keyword(s):  
Plasma Renin Activity ◽  
Plasma Flow ◽  
Free Water ◽  
Plasma Renin ◽  
Renal Perfusion ◽  
Renin Activity ◽  
Water Excretion ◽  
Transit Times ◽  
Abnormal Pattern ◽  
Intrarenal Distribution

1. The intrarenal distribution of plasma flow was determined with a technique based on the analysis of the transit time of sodium o-[131I]-iodohippurate through the kidney in 43 patients with cirrhosis with near-normal total renal perfusion. 2. Twenty-five of the patients had an abnormal pattern of transit times, suggesting a redistribution of plasma flow from outer cortical to juxtamedullary nephrons. 3. Plasma renin activity ranged from below normal to six times normal and high values were found only in patients showing an abnormal pattern of transit times. The latter was also found to be related to sodium retention and a reduced renal capacity to excrete free water.

Effect of an opiate antagonist on the responses of circulating catecholamines and the renin-aldosterone system to acute sympathetic stimulation by hand-grip in man

1986 ◽  
Vol 111 (2) ◽  
pp. 252-257 ◽  
Author(s):  
K. S. L. Lam ◽  
A. Grossman ◽  
P. Bouloux ◽  
P. L. Drury ◽  
G. M. Besser
Keyword(s):  
Blood Pressure ◽  
Plasma Renin Activity ◽  
Plasma Renin ◽  
Endogenous Opioids ◽  
Renin Activity ◽  
Mild Stress ◽  
Sympathetic Stimulation ◽  
Plasma Adrenaline ◽  
Hand Grip ◽  
Serum Aldosterone

Abstract. The effect of naloxone on the neurohumoral responses to acute sympathetic stimulation by sustained hand-grip in normal man was investigated. Six normal males were studied fasting at 08.30 h, on two occasions at 7-day intervals, with each subject sustaining 30% of his maximal hand-grip on a hand dynamometer for 5 min. Naloxone (8 mg bolus) in 20 ml normal saline, or saline alone, was given 5 min before hand-grip in a randomised double-blind cross-over trial. Blood was sampled for plasma renin activity, serum aldosterone and plasma catecholamines. The study was repeated in the absence of hand-grip. Sustained hand-grip produced significant elevations in mean blood-pressure, circulating adrenaline, noradrenaline and aldosterone. Naloxone, which had no effect on basal catecholamines, plasma renin activity or aldosterone, significantly enhanced the responses in plasma adrenaline, plasma renin activity and serum aldosterone to hand-grip. The increments in blood pressure and noradrenaline were not affected. These results suggest that endogenous opioids modulate the response of the sympathoadrenal and renin-aldosterone systems to acute sympathetic stimulation by a mild stress in man.

scholarly journals Renovascular hypertension using a modified two-kidney, one-clip approach in mice is not dependent on the α1 or α2 Na-K-ATPase ouabain-binding site

2011 ◽  
Vol 301 (3) ◽  
pp. F615-F621 ◽  
Author(s):  
John N. Lorenz ◽  
Valerie M. Lasko ◽  
Michelle L. Nieman ◽  
Thomas Damhoff ◽  
Vikram Prasad ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Artery ◽  
Binding Site ◽  
Renovascular Hypertension ◽  
Plasma Renin ◽  
Mutant Mice ◽  
Ouabain Binding ◽  
Α Subunit ◽  
Pressure Changes ◽  
2K1c Hypertension

Endogenous cardiotonic steroids, through their interaction with the ouabain-binding site of the Na-K-ATPase α-subunit, have been implicated in a variety of cardiovascular disease states including hypertension. We have previously shown that ACTH-induced hypertension is abolished in mutant mice expressing ouabain-resistant α1- and α2-subunits. To further evaluate hypertension resistance in these mutant mice, we examined blood pressure changes in a modified model of 2-kidney, 1-clip (2K1C) renovascular hypertension. To reliably generate 2K1C hypertension, we used polyvinyl tubing (inner diameter: ∼0.27 mm) to accurately gauge the degree of renal artery stenosis. Using this method, virtually all of the clipped mice became hypertensive and there was no incidence of apparent renal ischemia. By telemetry, in response to renal artery clipping, blood pressure in wild-type mice (α1 ouabain-resistant, α2 ouabain-sensitive) increased from 97 ± 3 to 136 ± 7 mmHg. In α1-resistant, α2-resistant mice, pressure increased from 93 ± 2 to 123 ± 4 mmHg, and in α1-sensitive, α2-resistant mice, blood pressure increased from 95 ± 2 to 139 ± 5 mmHg. Blood pressure changes were equivalent in all three groups. In sham mice, blood pressure did not change (96 ± 1 to 95 ± 2 mmHg). Renin mRNA expression was dramatically elevated in the left vs. the right kidney, and plasma renin concentration was elevated similarly in all genotypes. These data indicate that sensitivity of the α1- or α2-Na-K-ATPase binding site to cardiotonic steroids is not a prerequisite for the development of 2K1C renovascular hypertension. In addition, use of a polyurethane cuff to constrict the renal artery provides a reliable method for producing 2K1C hypertension in mice.

scholarly journals A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na+ retention

2013 ◽  
Vol 305 (12) ◽  
pp. F1697-F1704 ◽  
Author(s):  
Jacob Richards ◽  
Kit-Yan Cheng ◽  
Sean All ◽  
George Skopis ◽  
Lauren Jeffers ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Target Genes ◽  
Collecting Duct ◽  
Specific Rate ◽  
Wild Type ◽  
Α Subunit ◽  
Aldosterone Production

The circadian clock plays an important role in the regulation of physiological processes, including renal function and blood pressure. We have previously shown that the circadian protein period (Per)1 regulates the expression of multiple Na+ transport genes in the collecting duct, including the α-subunit of the renal epithelial Na+ channel. Consistent with this finding, Per1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. We have also recently demonstrated the potential opposing actions of cryptochrome (Cry)2 on Per1 target genes. Recent work by others has demonstrated that Cry1/2 regulates aldosterone production through increased expression of the adrenal gland-specific rate-limiting enzyme 3β-dehydrogenase isomerase (3β-HSD). Therefore, we tested the hypothesis that Per1 plays a role in the regulation of aldosterone levels and renal Na+ retention. Using RNA silencing and pharmacological blockade of Per1 nuclear entry in the NCI-H295R human adrenal cell line, we showed that Per1 regulates 3β-HSD expression in vitro. These results were confirmed in vivo: mice with reduced levels of Per1 had decreased levels of plasma aldosterone and decreased mRNA expression of 3β-HSD. We postulated that mice with reduced Per1 would have a renal Na+-retaining defect. Indeed, metabolic cage experiments demonstrated that Per1 heterozygotes excreted more urinary Na+ compared with wild-type mice. Taken together, these data support the hypothesis that Per1 regulates aldosterone levels and that Per1 plays an integral role in the regulation of Na+ retention.

Early fluid retention and severe acute mountain sickness

2005 ◽  
Vol 98 (2) ◽  
pp. 591-597 ◽  
Author(s):  
Jack A. Loeppky ◽  
Milton V. Icenogle ◽  
Damon Maes ◽  
Katrina Riboni ◽  
Helmut Hinghofer-Szalkay ◽  
...  
Keyword(s):  
Acute Mountain Sickness ◽  
Plasma Concentrations ◽  
Free Water ◽  
Plasma Renin ◽  
Barometric Pressure ◽  
Respiratory Alkalosis ◽  
Fluid Retention ◽  
Free Water Clearance ◽  
Water Excretion ◽  
Mountain Sickness

Field studies of acute mountain sickness (AMS) usually include variations in exercise, diet, and environmental conditions over days and development of clinically apparent edemas. The purpose of this study was to clarify fluid status in persons developing AMS vs. those remaining without symptoms during simulated altitude with controlled fluid intake, diet, temperature, and without exercise. Ninety-nine exposures of 51 men and women to reduced barometric pressure (426 mmHg = 16,000 ft. = 4,880 m) were carried out for 8–12 h. AMS was evaluated by Lake Louise (LL) and AMS-C scores near the end of exposure. Serial measurements included fluid balance, electrolyte excretions, and plasma concentrations, regulating hormones, and free water clearance. Comparison between 16 subjects with the lowest AMS scores near the end of exposure (“non-AMS”: mean LL = 1.0, range = 0–2.5) and 16 others with the highest AMS scores (“AMS”: mean LL = 7.4, range = 5–11) demonstrated significant fluid retention in AMS beginning within the first 3 h, resulting from reduced urine flow. Plasma Na+ decreased significantly after 6 h, indicating dilution throughout the total body water. Excretion of Na+ and K+ trended downward with time in both groups, being lower in AMS after 6 h, and the urine Na+-to-K+ ratio was significantly higher for AMS after 6 h. Renal compensation for respiratory alkalosis, plasma renin activity, aldosterone, and atrial natriuretic peptide were not different between groups, with the latter tending to rise and aldosterone falling with time of exposure. Antidiuretic hormone fell in non-AMS and rose in AMS within 90 min of exposure and continued to rise in AMS, closely associated with severity of symptoms and fluid retention.

scholarly journals Natriuretic peptides buffer renin-dependent hypertension

2014 ◽  
Vol 306 (12) ◽  
pp. F1489-F1498 ◽  
Author(s):  
Theo Demerath ◽  
Janina Staffel ◽  
Andrea Schreiber ◽  
Daniela Valletta ◽  
Frank Schweda
Keyword(s):  
Blood Pressure ◽  
Renovascular Hypertension ◽  
Natriuretic Peptide ◽  
Natriuretic Peptides ◽  
Plasma Renin ◽  
Control Mechanisms ◽  
Wild Type ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Independent Effects

The renin-angiotensin-aldosterone system and cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are opposing control mechanisms for arterial blood pressure. Accordingly, an inverse relationship between plasma renin concentration (PRC) and ANP exists in most circumstances. However, PRC and ANP levels are both elevated in renovascular hypertension. Because ANP can directly suppress renin release, we used ANP knockout (ANP−/−) mice to investigate whether high ANP levels attenuate the increase in PRC in response to renal hypoperfusion, thus buffering renovascular hypertension. ANP−/− mice were hypertensive and had reduced PRC compared with that in wild-type ANP+/+ mice under control conditions. Unilateral renal artery stenosis (2-kidney, 1-clip) for 1 wk induced similar increases in blood pressure and PRC in both genotypes. Unexpectedly, plasma BNP concentrations in ANP−/− mice significantly increased in response to two-kidney, one-clip treatment, potentially compensating for the lack of ANP. In fact, in mice lacking guanylyl cyclase A (GC-A−/− mice), which is the common receptor for both ANP and BNP, renovascular hypertension was markedly augmented compared with that in wild-type GC-A+/+ mice. However, the higher blood pressure in GC-A−/− mice was not caused by disinhibition of the renin system because PRC and renal renin synthesis were significantly lower in GC-A−/− mice than in GC-A+/+ mice. Thus, natriuretic peptides buffer renal vascular hypertension via renin-independent effects, such as vasorelaxation. The latter possibility is supported by experiments in isolated perfused mouse kidneys, in which physiological concentrations of ANP and BNP elicited renal vasodilatation and attenuated renal vasoconstriction in response to angiotensin II.

Renal function of gene-targeted mice lacking both SGK1 and SGK3

2006 ◽  
Vol 290 (4) ◽  
pp. R945-R950 ◽  
Author(s):  
Florian Grahammer ◽  
Ferruh Artunc ◽  
Diana Sandulache ◽  
Rexhep Rexhepaj ◽  
Björn Friedrich ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Hair Growth ◽  
Plasma Aldosterone ◽  
Standard Diet ◽  
Wild Type ◽  
Electrolyte Excretion ◽  
Deficient Diet ◽  
Low Salt ◽  
Salt Depletion ◽  
Nacl Excretion

Serum- and glucocorticoid-inducible kinase (SGK) 1 and SGK3 share the ability to upregulate several ion channels, including the epithelial Na+ channel. Whereas SGK1 is under genomic control of mineralocorticoids and glucocorticoids, SGK3 is constitutively expressed. The SKG1-knockout ( sgk1−/−) mouse is seemingly normal when it is fed a standard diet, but its ability to retain NaCl is impaired when it is fed a salt-deficient diet. In the SGK3-knockout ( sgk3−/−) mouse fed standard and salt-deficient diets, hair growth is strikingly delayed but NaCl excretion is normal. Thus the possibility was considered that SGK1 and SGK3 could mutually replace each other, thus preventing severe NaCl loss in sgk1−/− and sgk3−/− mice. We crossed SGK1- and SGK3-knockout mice and compared renal electrolyte excretion of the double mutants ( sgk1−/−/ sgk3−/−) with that of their wild-type littermates ( sgk1+/+/ sgk3+/+). Similar to sgk3−/− mice, the sgk1−/−/ sgk3−/− mice display delayed hair growth. Blood pressure was slightly, but significantly ( P < 0.03), lower in sgk1−/−/ sgk3−/− (102 ± 4 mmHg) than in sgk1+/+/ sgk3+/+ (114 ± 3 mmHg) mice, a difference that was maintained in mice fed low- and high-salt diets. Plasma aldosterone concentrations were significantly ( P < 0.01) higher in sgk1−/−/ sgk3−/− than in sgk1+/+ sgk3+/+ mice fed control (511 ± 143 vs. 143 ± 32 pg/ml) and low-salt (1,325 ± 199 vs. 362 ± 145 pg/ml) diets. During salt depletion, absolute and fractional excretions of Na+ were significantly ( P < 0.01) higher in sgk1−/−/ sgk3−/− (1.2 ± 0.2 μmol/24 h g body wt, 0.12 ± 0.03%) than in sgk1+/+/ sgk3+/+ (0.4 ± 0.1 μmol/24 h g body wt, 0.04 ± 0.01%) mice. The sgk1−/−/ sgk3−/− mice share the delayed hair growth with sgk3−/− mice and the modestly impaired renal salt retention with sgk1−/− mice. Additional lack of the isoform kinase does not substantially compound the phenotype for either property.

Role of the renin–angiotensin–aldosterone system in collecting duct-derived endothelin-1 regulation of blood pressureThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

2008 ◽  
Vol 86 (6) ◽  
pp. 329-336 ◽  
Author(s):  
Yuqiang Ge ◽  
Yufeng Huang ◽  
Donald E. Kohan
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Similar Degree ◽  
Water Excretion ◽  
Renin Angiotensin ◽  
Endothelin 1 ◽  
And Control ◽  
Renin Content

Renal collecting duct (CD)-specific knockout of endothelin-1 (ET-1) causes hypertension and impaired Na excretion. A previous study noted failure to suppress the renin–angiotensin–aldosterone axis in these knockout (KO) mice, hence the current investigation was undertaken to examine the role of this system in CD ET-1 KO. Renal renin content was similar in kidneys from CD ET-1 KO and control mice during normal Na intake; high-Na intake suppressed renal renin content to a similar degree in KO and control. Plasma renin concentrations paralleled changes in renal renin content. Valsartan, an angiotensin receptor blocker (ARB), abolished the hypertension in CD ET-1 KO mice during normal Na intake. High-Na intake + ARB treatment increased blood pressure in CD ET-1 KO, but not in controls. High-Na intake was associated with reduced Na excretion in CD ET-1 KO animals, but no changes in water excretion or creatinine clearance were noted. Spironolactone, an aldosterone antagonist, also normalized blood pressure in CD ET-1 KO mice during normal Na intake, whereas high-Na intake + spironolactone raised blood pressure only in CD ET-1 KO animals. In summary, hypertension in CD ET-1 KO is partly due to angiotensin II and aldosterone. We speculate that CD-derived ET-1 may regulate, via a novel pathway, renal renin production.

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