Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter in vascular smooth muscle

Jiang, Gengru; Akar, Fatma; Cobbs, Scott L.; Lomashvilli, Koba; Lakkis, Randala; Gordon, Frank J.; Sutliff, Roy L.; O’Neill, W. Charles

doi:10.1152/ajpheart.00695.2003

Cited by 19 publications

(19 citation statements)

References 39 publications

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“…25,26 WNK1 notably phosphorylates synaptotagmin 2, 25 modulating its plasma membrane binding and possibly affecting the release from or the insertion in the plasma membrane of several vesicle-associated proteins, such as ionic cotransporters, which, if not integrated correctly in the membrane, could possibly be targeted for degradation. Interestingly, NKCC1 has also been shown to regulate arterial BP 27,28 and to mediate ␣ 1 -adrenergic agonist-induced contractions in several models, 29,30 as well as myogenic response in mouse mesenteric arteries 31 and rat arterioles, 32 to the same extent as what we observed in Wnk1 ϩ/Ϫ mice. Taken together, this suggests that SPAK and NKCC1 could represent one of the signaling pathways involved downstream of L-WNK1 during Phe and myogenic vasoconstrictions.…”

Section: Discussionsupporting

confidence: 80%

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α ₁ -Adrenergic Stimulation in Mice

et al. 2011

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Abstract-Gain-of-function mutations in the human WNK1 (with-no-lysine[K]1) gene are responsible for a monogenic form of arterial hypertension, and WNK1 polymorphisms have been associated with common essential hypertension. The role of WNK1 in renal ionic reabsorption has been established, but no investigation of its possible influence on vascular tone, an essential determinant of blood pressure, has been performed until now. WNK1 complete inactivation in the mouse is embryonically lethal. We, thus, examined in Wnk1 ϩ/Ϫ haploinsufficient adult mice whether WNK1 could regulate in vivo vascular tone and whether this was correlated with blood pressure variation. Wnk1 ϩ/Ϫ mice displayed a pronounced decrease in blood pressure responses in vivo and in vascular contractions ex vivo following ␣ 1 -adrenergic receptor activation with no change in basal blood pressure and renal function. We also observed a major loss of the pressure-induced contractile (myogenic) response in Wnk1 ϩ/Ϫ arteries associated with a specific alteration of the smooth muscle cell contractile function. These alterations in vascular tone were associated with a decreased phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na ϩ -K ϩ -2Cl Ϫ cotransporter 1) in Wnk1 ϩ/Ϫ arteries. Our study identifies a novel and major role for WNK1 in maintaining in vivo blood pressure and vasoconstriction responses specific to ␣ 1 -adrenergic receptor activation. Our findings uncover a vascular signaling pathway linking ␣ 1 -adrenergic receptors and pressure to WNK1, SPAK, and NKCC1 and may, thus, significantly broaden the comprehension of the regulatory mechanisms of vascular tone in arterial hypertension. 1 In addition, several common polymorphisms at the WNK1 locus have been associated with essential hypertension. 2 Because Familial Hyperkalemic Hypertension is associated with renal dysfunction, the role of this novel serine-threonine kinase has been extensively studied in renal ion homeostasis. This allowed to demonstrate that WNK1 is part of a novel signaling pathway involved in the complex regulation of sodium, potassium, and chloride balance in the kidney (for review see Reference 3 ).WNK1 gives rise to 2 different isoforms with different expression patterns. The kidney-specific isoform of WNK1 (KS-WNK1) is specifically expressed in the distal nephron, 4 whereas the long-WNK1 (L-WNK1) isoform is expressed ubiquitously. 5,6 Investigations of the mechanisms by which L-WNK1 could participate in the control of blood pressure (BP) have been mostly limited to in vitro models of renal transport, 3 and its mechanism of BP regulation in vivo has not yet been elucidated. Indeed, in vivo WNK1 regulation of BP does not seem to be exclusively mediated by its renal action. Lexicon Pharmaceuticals, Inc, generated mice constitutively lacking WNK1 using a gene-trap strategy. 7 This mouse model thus represents the mirror image of the human disease for which hypertension has been shown to be caused by gain-offu...

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Section: Discussionsupporting

confidence: 80%

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α ₁ -Adrenergic Stimulation in Mice

et al. 2011

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“…6 In addition, the expression or activity of NKCC1 is upregulated in a variety of hypertensive models. 4,[7][8][9][10] angiotensin II (Ang II) increases the activity of cation-coupled Cl À cotransporters, including NKCC1, through STE20/SPS1-related proline/alanine-rich kinase. 11 However, the mechanism by which Ang II stimulates NKCC1 is not yet clear.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the Na+-K+-2Cl− cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats

et al. 2012

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The Na þ -K þ -2Cl À cotransporter 1 (NKCC1) is upregulated in diverse models of hypertension. We hypothesized that NKCC1 is upregulated via histone modification in the aortas of angiotensin II (Ang II)-induced hypertensive rats. An osmotic mini-pump containing Ang II was implanted in the subcutaneous tissues of the backs of Sprague-Dawley (SD) rats for 7 days. The systolic blood pressure was recorded every day by the tail-cuff method. On days 3 and 7, the mesenteric arteries were excised, cut into rings, mounted in organ baths and subjected to vascular contraction. The levels of Nkcc1 mRNA and protein in the aortas were measured using real-time PCR and Western blotting, respectively. The histone modifications and recruited proteins at the Nkcc1 promoter were determined by chromatin immunoprecipitation. The inhibition of concentration-response curves to phenylephrine by bumetanide, an inhibitor of NKCCs, was greater in Ang II-infused rats than in sham-operated (sham) rats . The levels of Nkcc1 mRNA and protein in the aortas increased gradually as Ang II was infused into the rats. Acetylated histone H3 (H3Ac), an activating histone code, was increased but trimethylated histone H3 at lysine 27 (H3K27me3), a repressive histone code, was greatly decreased in Ang II-infused rats compared with sham. RNA polymerase II was recruited to the Nkcc1 promoter with increased KDM6b. We conclude that the NKCC1 is upregulated via histone modification in the aortas of Ang II-induced hypertensive rats. Thus, we suggest that this ion transporter is epigenetically upregulated by histone modification or DNA demethylation upon the development of hypertension.

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“…Expression and activity of NKCC1 are known to be upregulated by high blood pressure in diverse forms of hypertensive models [4][5][6][7][8]. In this study, Ang II infusion with a pressor (0.7 mg/kg per day) dose [28] resulted in an increase of blood pressure by more than 30 mmHg after 7 days of infusion, compared with sham (Fig.…”

Section: Nkcc1 Upregulation By Sp1 In Hypertensionmentioning

confidence: 56%

“…Although 24-h mean arterial blood pressure and heart rate measured by radiotelemetry do not differ between Nkcc1 À/ À and wild-type mice, the blood pressure of Nkcc1 À/À mice is more sensitive to increases or decreases of sodium intake [3]. Upregulated expression or activity of NKCC1 also occurs in a variety of hypertensive models [4][5][6][7][8]. In addition, several research groups have proposed that augmented ion fluxes mediated by NKCC1 detected in erythrocyte and VSMC from spontaneously hypertensive rat (SHR) and Milan hypertensive strain (MSH) contribute to the pathogenesis of hypertension [9,10].…”

Section: Introductionmentioning

confidence: 99%

Recruitment of Specificity Protein 1 by CpG hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in hypertensive rats

Cho¹,

Lee

Kim³

et al. 2013

Journal of Hypertension

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Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter in vascular smooth muscle

Cited by 19 publications

References 39 publications

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α ₁ -Adrenergic Stimulation in Mice

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α ₁ -Adrenergic Stimulation in Mice

Upregulation of the Na+-K+-2Cl− cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats

Recruitment of Specificity Protein 1 by CpG hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in hypertensive rats

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Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter in vascular smooth muscle

Cited by 19 publications

References 39 publications

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α 1 -Adrenergic Stimulation in Mice

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α 1 -Adrenergic Stimulation in Mice

Upregulation of the Na+-K+-2Cl− cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats

Recruitment of Specificity Protein 1 by CpG hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in hypertensive rats

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WNK1 Regulates Vasoconstriction and Blood Pressure Response to α ₁ -Adrenergic Stimulation in Mice

WNK1 Regulates Vasoconstriction and Blood Pressure Response to α ₁ -Adrenergic Stimulation in Mice