Promoter hypomethylation upregulates Na+–K+–2Cl− cotransporter 1 in spontaneously hypertensive rats

Lee, Hae-Ahm; Baek, Inji; Seok, Young Mi; Yang, Enyue; Cho, Hyunmin; Lee, Dong-Youb; Hong, Su Hyung; Kim, In Kyeom

doi:10.1016/j.bbrc.2010.04.074

Cited by 46 publications

(36 citation statements)

References 29 publications

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“…16,26 Recently, our group reported that CpG hypermethylation on the Nkcc1 promoter reduced its transcription in the cerebral cortex 27 and in areas of the cardiovascular system, such as the aorta and heart, in normotensive rats. 12 Treatment with 5-aza-cytidine, an inhibitor of DNA methyltransferase, or trichostatin A, an inhibitor of histone deacetylase, upregulated its transcription in the cerebral cortex during postnatal maturation. 27 In this study, however, the Nkcc1 promoter in SD rats was mostly unmethylated, indicating that the methylation status of the promoter shows species and tissue specificity.…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis was performed as previously described. 12 The expression levels were quantified by optical densitometry using ImageJ software (http:// rsbweb.nih.gov).…”

Section: Protein Extraction and Western Blottingmentioning

confidence: 99%

“…12 Furthermore, the maintenance of hypomethylation at the Nkcc1 promoter resulting from low DNA methyltransferase activity has an important role in the upregulation of NKCC1 during the development of spontaneous hypertension. 13 Because the Nkcc1 promoter region in the aortas of SD rats is almost unmethylated, histone modification is another plausible epigenetic mechanism for the upregulation of Nkcc1 expression during a BP increase.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…Western blot analysis was performed as previously described. 12 The expression levels were quantified by optical densitometry using ImageJ software (http:// rsbweb.nih.gov).…”

Section: Protein Extraction and Western Blottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…This provides new ideas and methods for the treatment of different diseases. Previous studies have shown a close relationship between a number of candidate hypertension genes and DNA methylation in the development of hypertension [29], such as 11β-HSD2 [3], ACE [30], NKCC1 [4], and adipocyte determination and differentiation factor-l ( ADD-l ) [31]. In addition, peripheral blood genome-wide DNA methylation levels are significantly altered between patients with hypertension and healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Hypertension has been correlated with abnormal levels of candidate gene methylation [3]. Previous experiments have shown that the aortic and cardiac tissue Na + /K + /Cl - cotransporter protein 1 (NKCC1) demonstrated a low level of promoter methylation, which led to an increase of NKCC1 gene expression and promoted the formation of hypertension in a spontaneously hypertensive rat model [4]. Angiotensin-converting enzyme (ACE) gene methylation is involved in hypertension and other cardiovascular diseases [5,6].…”

Section: Introductionmentioning

confidence: 99%

Hypomethylation of the Angiotensin II Type I Receptor (<b><i>AGTR1</i></b>) Gene Along with Environmental Factors Increases the Risk for Essential Hypertension

Lin

et al. 2017

Cardiology

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Objectives: The present study aimed to evaluate the hypertension status of community residents, analyze environmental and epigenetic factors, and propose prevention measures for hypertension. Methods: In our study, different methylation levels were distinguished utilizing melting temperature (T_m) values in both the case and the control group. Multiple logistic regression analysis was used to estimate the risk of having essential hypertension (EH) between hypertensive and nonhypertensive participants. A receiver-operating characteristic curve was used to analyze T_m cutoff levels of methylation. Results: The average DNA T_m was 71.784 with a standard deviation of 0.210. The T_m value of community residents (Fujian, China) was inversely correlated with systolic and diastolic blood pressure. Student t test analysis showed a clear separation in T_m expression levels between the hypertensive and the control group (p < 0.05). The T_m value was lower in the hypertension group than in the normotensive group. Multivariate regression analysis showed that high levels of DNA methylation were a protective factor in hypertension with adjustment of demographic and environmental factors, whereas when the T_m value increased by 0.1 units, the risk of hypertension was reduced by 0.652 times. Patients that smoked and consumed an irregular diet demonstrated a lower degree of methylation in the presence of hypertension. Conclusions: DNA methylation affects the risk for the development of hypertension; therefore, epigenetic markers could be used to measure hypertension levels to help elucidate the pathogenesis of EH.

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Na⁺‐K⁺‐2Cl⁻Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia

Delpire¹,

Gagnon²

2018

Comprehensive Physiology

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Two genes encode the Na -K -2Cl cotransporters, NKCC1 and NKCC2, that mediate the tightly coupled movement of 1Na , 1K , and 2Cl across the plasma membrane of cells. Na -K -2Cl cotransport is driven by the chemical gradient of the three ionic species across the membrane, two of them maintained by the action of the Na /K pump. In many cells, NKCC1 accumulates Cl above its electrochemical potential equilibrium, thereby facilitating Cl channel-mediated membrane depolarization. In smooth muscle cells, this depolarization facilitates the opening of voltage-sensitive Ca channels, leading to Ca influx, and cell contraction. In immature neurons, the depolarization due to a GABA-mediated Cl conductance produces an excitatory rather than inhibitory response. In many cell types that have lost water, NKCC is activated to help the cells recover their volume. This is specially the case if the cells have also lost Cl . In combination with the Na /K pump, the NKCC's move ions across various specialized epithelia. NKCC1 is involved in Cl -driven fluid secretion in many exocrine glands, such as sweat, lacrimal, salivary, stomach, pancreas, and intestine. NKCC1 is also involved in K -driven fluid secretion in inner ear, and possibly in Na -driven fluid secretion in choroid plexus. In the thick ascending limb of Henle, NKCC2 activity in combination with the Na /K pump participates in reabsorbing 30% of the glomerular-filtered Na . Overall, many critical physiological functions are maintained by the activity of the two Na -K -2Cl cotransporters. In this overview article, we focus on the functional roles of the cotransporters in nonpolarized cells and in epithelia. © 2018 American Physiological Society. Compr Physiol 8:871-901, 2018.

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Promoter hypomethylation upregulates Na+–K+–2Cl− cotransporter 1 in spontaneously hypertensive rats

Cited by 46 publications

References 29 publications

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

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

Hypomethylation of the Angiotensin II Type I Receptor (<b><i>AGTR1</i></b>) Gene Along with Environmental Factors Increases the Risk for Essential Hypertension

Na⁺‐K⁺‐2Cl⁻Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia

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Promoter hypomethylation upregulates Na+–K+–2Cl− cotransporter 1 in spontaneously hypertensive rats

Cited by 46 publications

References 29 publications

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

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

Hypomethylation of the Angiotensin II Type I Receptor (<b><i>AGTR1</i></b>) Gene Along with Environmental Factors Increases the Risk for Essential Hypertension

Na+‐K+‐2Cl−Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia

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Na⁺‐K⁺‐2Cl⁻Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia