Differential upregulation of rat Na-K-Cl cotransporter, rBSC1, mRNA in the thick ascending limb of Henle in different pathological conditions

Marumo, Rie; Kaizuma, Sakiko; Nogae, Shoji; Kanazawa, Masayuki; Kimura, Tokihisa; Saito, Takao; Ito, Sadayoshi; Matsubara, Mitsunobu

doi:10.1046/j.1523-1755.1998.00051.x

Cited by 41 publications

(46 citation statements)

References 19 publications

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“…63,64 In addition, studies in rats with mild heart failure have found increased expression of the Na-K-2Cl cotransport in the thick ascending limb of Henle's loop, a phenomenon associated with not only augmented sodium but also water reabsorption capacity. 65,66 As we indicated previously, 9 it is unlikely that exact mechanisms and gene variants causing the sodium-sensitive type hypertension in laboratory animals are also responsible for sodium sensitivity in blacks, but the physiological principles that govern renal sodium and water homeostasis are shared by all mammals. Thus, these animal models support the thesis that an increase in the activity of Na-K-2Cl cotransport in the thick ascending limb of Henle's loop augments not only sodium but also water reabsorption.…”

Section: Further Clues For Sodium Sensitivity In Blacks Based On Potamentioning

confidence: 89%

Urinary Potassium Excretion and Sodium Sensitivity in Blacks

2004

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Abstract-Based on racial differences in urinary potassium excretion and responses to diuretics, we present a model suggesting that a major cause of sodium sensitivity in blacks is an augmented activity of the Na-K-2Cl cotransport in the thick ascending limb of Henle's loop. This would result in an increased ability to conserve not only sodium but also water, and an upward and rightward shift in the operating point of tubuloglomerular feedback, which may cause an increase in the glomerular capillary hydraulic pressure and predilection to glomerular injury with and without hypertension. In this sense, the biological implication of sodium sensitivity in blacks and in humans in general has ramifications above and beyond salt-evoked increase in blood pressure. Key Words: blacks Ⅲ hypertension, essential Ⅲ kidney Ⅲ potassium Ⅲ sodium B lood pressure of a subset of the human population rises as a result of an increase in the intake of salt (sodium chloride). 1 Individuals who manifest this trait are salt sensitive. As sodium (and chloride) balance must be preserved to sustain life, salt-sensitive and salt-resistant subjects maintain sodium balance. What distinguishes salt-sensitive from saltresistant subjects is that in the face of a high-salt intake, salt-sensitive subjects raise their blood pressure, ultimately maintaining sodium balance by resorting to pressure natriuresis. 2 However, a habitually high salt consumption in susceptible individuals may exert biological effects other than salt-evoked blood pressure elevation, including left ventricular hypertrophy, stiffness of conduit arteries, and stroke. [3][4][5] The kidneys are the main player in salt sensitivity, but mechanisms causing this trait are a matter of conjecture. Lessons from rare, monogenic forms of hypertension and hypotension arising from abnormalities in renal sodium handling 6 -8 suggest that salt sensitivity need not be a single entity; rather, it is probably a clinical manifestation of a number of renal disorders that result in altered electrolyte homeostasis and thus blood pressure elevation.Salt sensitivity in blacks has begged for a physiological explanation ever since the predilection of this group to essential hypertension and progressive renal damage has come to light. In a previous communication, we offered a paradigm that explains salt sensitivity in blacks. 9 This article further expands the model by proposing that the differences in renal potassium handling between blacks and whites reflect ethnic variation in the fractional reabsorption of sodium in specific renal tubular segments. Moreover, we propose that mechanisms in the renal regulation of sodium may explain the predisposition of blacks to sodium-induced elevation of blood pressure and also to sodium-induced glomerular damage. Here, we refer to salt sensitivity as "sodium sensitivity," albeit some research has suggested that not only sodium but also chloride, potassium, and perhaps other nutrients may contribute to the salt-sensitivity trait. 10 -13 Although irrefutable evidenc...

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Section: Further Clues For Sodium Sensitivity In Blacks Based On Potamentioning

confidence: 89%

Urinary Potassium Excretion and Sodium Sensitivity in Blacks

2004

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“…In support of this concept, recent studies demonstrate that enhanced expression of BSC-1 in the TAL causes sodium retention in rats with congestive heart failure. 3 Moreover, BSC-1 is upregulated in rats with small-to-moderate myocardial infarctions, 4 dehydration, and cardiac failure 5 and in an animal model of liver cirrhosis. 6 Moreover, our results in the spontaneously hypertensive rat (SHR) show that expression of BSC-1 is also elevated in this animal model of essential hypertension and that the natriuretic response to furosemide (which blocks BSC-1) is significantly higher in the SHR compared with its normotensive counterpart, suggesting that BSC-1 could be involved in the development and/or maintenance of hypertension in the SHR.…”

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confidence: 99%

Norepinephrine, via β-Adrenoceptors, Regulates Bumetanide-Sensitive Cotransporter Type 1 Expression in Thick Ascending Limb Cells

Sonalker

Jackson

2007

Hypertension

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Abstract-The sympathetic nervous system, via norepinephrine, regulates renal sodium transport, and chronic sympathetic activation causes sustained increases in blood pressure by reducing sodium excretion. Our previous studies show that chronic norepinephrine infusion increases the abundance of the bumetanide-sensitive cotransporter type 1, the apical sodium transporter of the thick ascending limb of Henle's loop. The present study was initiated to elucidate the mechanisms by which norepinephrine regulates the protein levels of this transporter in an immortalized thick ascending limb epithelial cell line. Treatment with norepinephrine, either alone or in the presence of actinomycin D or cycloheximide, had no effect on cotransporter mRNA levels. Treatment with norepinephrine, however, increased bumetanide-sensitive cotransporter type 1 protein levels (70% increase versus control; Pϭ0.012), and pretreatment with cycloheximide blocked the effect of norepinephrine on bumetanide-sensitive cotransporter type 1 protein levels. To further elucidate the mechanism, thick ascending limb cells were treated with norepinephrine in the presence of phentolamine (␣-adrenoceptor blocker), propranolol (␤-adrenoceptor blocker), SQ22536 (adenylyl cyclase inhibitor), PD098059 (mitogen-activated protein kinase pathway inhibitor), H-89 (protein kinase A inhibitor), or staurosporine (protein kinase C inhibitor). Treatment with propranolol, SQ22536, and H-89 abolished the effects of norepinephrine on bumetanide-sensitive cotransporter type 1 protein levels, whereas staurosporine had no effect. Treatment with PD098059 partially inhibited the effects of norepinephrine (40% decrease versus norepinephrine; Pϭ0.03), and treatment with phentolamine potentiated the effects of norepinephrine (30% increase versus norepinephrine; Pϭ0.02) on bumetanide-sensitive cotransporter type 1 protein levels. We conclude that regulation of bumetanide-sensitive cotransporter type 1 by norepinephrine proceeds via the ␤-adrenoceptor receptor-cAMP-protein kinase A pathway that involves in part mitogen-activated protein kinases and that ␣-adrenoceptor activation negatively regulates bumetanidesensitive cotransporter type 1 protein levels. Key Words: BSC-1/NKCC2 Ⅲ thick ascending limb Ⅲ norepinephrine Ⅲ ␣-adrenoceptor Ⅲ ␤-adrenoceptor Ⅲ cAMP Ⅲ protein kinase A Ⅲ cAMP T he bumetanide-sensitive cotransporter type 1 (BSC-1) Na-K-2Cl cotransporter is the principal apical Na ϩ entry pathway in the thick ascending limb (TAL). 1,2 Therefore long-term dysregulation of BSC-1 may contribute to longterm dysregulation of arterial blood pressure. In support of this concept, recent studies demonstrate that enhanced expression of BSC-1 in the TAL causes sodium retention in rats with congestive heart failure. 3 Moreover, BSC-1 is upregulated in rats with small-to-moderate myocardial infarctions, 4 dehydration, and cardiac failure 5 and in an animal model of liver cirrhosis. 6 Moreover, our results in the spontaneously hypertensive rat (SHR) show that expression of BSC-1 is also ele...

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“…Moreover, BSC-1 is up-regulated in rats with small to moderate myocardial infarctions (Nogae et al, 2000), dehydration, and cardiac failure (Marumo et al, 1998). Finally, mutations in the NKCC2 gene, which encodes BSC-1 presumably by inducing a loss of function of the transporter, result in Bartter's syndrome, an inherited disease characterized by hypokalemic metabolic alkalosis, hypercalciuria, salt wasting, and volume depletion resulting in hypotension (Simon et al, 1996;Vargas-Poussou et al, 1998).…”

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Increased Expression of the Sodium Transporter BSC-1 in Spontaneously Hypertensive Rats

Sonalker

Tofovic²,

Jackson³

2004

J Pharmacol Exp Ther

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The purpose of this study was to compare the expression of BSC-1 (bumetanide-sensitive Na ϩ -K ϩ -2Cl Ϫ cotransporter) in kidneys of spontaneously hypertensive rats (SHR) versus Wistar-Kyoto (WKY) rats by immunoblotting and reverse transcription-polymerase chain reaction. To determine the specificity of any observed changes in BSC-1 expression, we also compared expression of the thiazide sensitive Na ϩ -Cl Ϫ cotransporter (TSC), the type-3 Na ϩ -H ϩ exchanger (NHE-3), Na ϩ -K ϩ -ATPase-␣ 1 , the inwardly rectifying K ϩ channel (ROMK-1), the type-1 Na ϩ -HCO 3 Ϫ cotransporter (NBC-1), aquaporin-1, and aquaporin-2. Analyses were performed on outer cortex, outer medulla, and inner medulla. BSC-1 protein was detected in outer medulla and was markedly (6-fold) higher in SHR. TSC protein was detected in the cortex and was not overexpressed in SHR. Aquaporin-1 protein was detected in all three regions and was not overexpressed in SHR. Aquaporin-2 and ROMK-1 proteins were detected in all three regions, but were moderately elevated (2-fold) only in the SHR inner medulla. Na ϩ -K ϩ -ATPase and NHE-3 proteins were detected in all three regions. Na ϩ -K ϩ -ATPase-␣ 1 was modestly (25%) increased in SHR outer and inner medulla, whereas NHE-3 was moderately (2-fold) increased in the SHR cortex and inner medulla. NBC-1 protein was detected only in the cortex and was higher (2-fold) in SHR. mRNA levels of BSC-1, aquaporin-2, and ROMK-1 were not elevated in SHR, indicating a post-translational mechanism of protein overexpression. High-dose furosemide increased fractional sodium excretion more in SHR than WKY (3-fold). We conclude that increased expression of BSC-1, and to a lesser extent, aquaporin-2, ROMK-1, NHE-3, and NBC-1 may contribute to the pathogenesis of hypertension in the SHR.

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Differential upregulation of rat Na-K-Cl cotransporter, rBSC1, mRNA in the thick ascending limb of Henle in different pathological conditions

Abstract: rBSC1 is differentially upregulated in different pathological conditions.

Cited by 41 publications

References 19 publications

Urinary Potassium Excretion and Sodium Sensitivity in Blacks

Urinary Potassium Excretion and Sodium Sensitivity in Blacks

Norepinephrine, via β-Adrenoceptors, Regulates Bumetanide-Sensitive Cotransporter Type 1 Expression in Thick Ascending Limb Cells

Increased Expression of the Sodium Transporter BSC-1 in Spontaneously Hypertensive Rats

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