A G-quadruplex nanoswitch in the SGK1 promoter regulates isoform expression by K+/Na+ balance and resveratrol binding

Chen, Mengjie; Chen, Qi; Li, Yirui; Yang, Zhenjun; Taylor, Ethan Will; Zhao, Lijun

doi:10.1016/j.bbagen.2020.129778

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…An overall increase in BG4 signal was reported in response to treatment, confirming RSV is targeting G4s at the genomic level. Other studies have also described RSV as a G4 ligand, but only for specific G4s in an in vitro setting; moreover, in these studies G4 targeting was not associated with a direct modulation of gene expression (27)(28)(29). As a consequence of G4 targeting, G4 ligands exert DNA damage and cell cycle arrest (30), both of which have been reported in this study.…”

Section: Discussionsupporting

confidence: 66%

Resveratrol targets G-quadruplexes to exert its pharmacological effects

Soriano-Lerma,

Sánchez-Martín,

Murciano-Calles

et al. 2024

Preprint

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Resveratrol (RSV) is one of the most studied and used biomolecules, for which many pharmacological effects targeting multiple tissues have been described. However, a common underlying mechanism driving its full pharmacological activity has not been elucidated to date. G-quadruplexes (G4s) are non-canonical nucleic acid structures found in promoters and involved in controlling gene transcription. This study demonstrates a G4-dependent mode of action for RSV, explaining its multi-target traits. RSV was shown to stabilise cellular G4s, which accumulate around double strand breaks (DSBs) in the promoters of differentially expressed genes (DEGs). G4 targeting triggers DNA damage and controls gene expression. Unravelling the main mode of action of RSV will be helpful to improve its therapeutic potential in a wide variety of health scenarios.

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Section: Discussionsupporting

confidence: 66%

Resveratrol targets G-quadruplexes to exert its pharmacological effects

Soriano-Lerma,

Sánchez-Martín,

Murciano-Calles

et al. 2024

Preprint

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“…Previous studies have showed that a lack of SGK1 could protect against high-salt diet-induced hypertension and prevent development of hypoxia-induced pulmonary arterial hypertension ( 37 , 38 ), while upregulation of SGK1 in the kidneys could upregulate ENaC expression, promoting sodium reabsorption and decreasing renal sodium excretion ( 14 , 15 ). In addition, our previous studies showed that glucocorticoids promote expression of NPR1, decrease the expression of SGK1 and improve the pathological state of water and sodium retention in mice with heart failure ( 20 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

“…Serum glucocorticoid-regulated kinase 1 (SGK1) upregulates expression of the epithelial sodium channel (ENaC), promoting sodium reabsorption and decreasing renal sodium excretion ( 14 , 15 ). The expression of NPR1 is positively regulated by SGK1 and NPR1 participates in renal sodium excretion ( 16 ), but whether NPR1 can regulate SGK1 expression, especially in the kidney, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoids ameliorate cardiorenal syndrome through the NPR1/SGK1 pathway in natriuretic peptide receptor A‑heterozygous mice

Huang

et al. 2023

Exp Ther Med

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Natriuretic peptides, which are produced by the heart, bind to natriuretic peptide receptor A (NPR1 encoded by natriuretic peptide receptor 1 gene) and cause vasodilation and natriuresis. Thus, they serve an important role in regulating blood pressure. In the present study, microinjection of CRISPR associated protein 9/single guide RNA into fertilized C57BL/6N mouse eggs was performed to generate filial generation zero (F0) Npr1 knockout homozygous mice (Npr1 -/- ). F0 mice mated with wild-type (WT) mice to obtain F1 Npr1 knockout heterozygous mice with stable heredity (Npr1 +/- ). F1 self-hybridization was used to expand the population of heterozygous mice (Npr1 +/- ). The present study performed echocardiography to investigate the impact of NPR1 gene knockdown on cardiac function. Compared with those in the WT group (C57BL/6N male mice), the left ventricular ejection fraction, myocardial contractility and renal sodium and potassium excretion and creatinine-clearance rates were decreased, indicating that Npr1 knockdown induced cardiac and renal dysfunction. In addition, expression of serum glucocorticoid-regulated kinase 1 (SGK1) increased significantly compared with that in WT mice. However, glucocorticoids (dexamethasone) upregulated NPR1 and inhibited SGK1 and alleviated cardiac and renal dysfunction caused by Npr1 gene heterozygosity. SGK1 inhibitor GSK650394 ameliorate cardiorenal syndrome by suppressing SGK1. Briefly, glucocorticoids inhibited SGK1 by upregulating NPR1, thereby ameliorating cardiorenal impairment caused by Npr1 gene heterozygosity. The present findings provided novel insight into the understanding of cardiorenal syndrome and suggested that glucocorticoids targeting the NPR1/SGK1 pathway may be a potential therapeutic target to treat cardiorenal syndrome.

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“…In addition, SGK1 regulates the expression of NKCCs, NCC and NHE3 [108][109][110][111][112][113]. Evidences from experiments in vivo certified that high sodium intake up-regulates SGK1/ENaC pathway, leading to salt-sensitive hypertension [114]. In contrary, SGK1 deficiency prevents the occurrence of hypertension caused by a high-fat/high-fructose diet [104].…”

Section: Two Important Kinases Regulating Kidney Ion Channelsmentioning

confidence: 99%

Kidney ion handling genes and their interaction in blood pressure control

Yang

Han

et al. 2022

Bioscience Reports

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Hypertension affects 30% of adults and is the leading risk factor for cardiovascular disease. Kidney sodium reabsorption plays a vital role in the initial stage and development of essential hypertension. It has been extensively reported that the variants of kidney ion handling genes are associated to blood pressure, and clinical features of hypertension. However, the underlying mechanisms by which these variants alter protein function are rarely summarized. In addition, the variation of one single gene is often limited to induce a significant effect on blood pressure. In the past few decades, the influence by genes × genes (G × G) and/or genotype × environment (G × E) interactions on a given trait, for example blood pressure, have been widely considered, especially in studies on polygenic genetic traits. In this review, we discuss the progress in genetics studies on kidney ion handling genes, encoding Na+ channels (NCC, NKCC2, ENaCs), K+ channel (ROMK), and Cl- channels (Pendrin, CLC-Kb), respectively, and their upstream kinases, WNKs and SGK1. We seek to clarify how these genes are involved in kidney sodium absorption and influence blood pressure, especially emphasizing the underlying mechanisms by which genetic variants alter protein functions and interaction in blood pressure regulation. This review aims to enhance our understanding of the important role of kidney ion handling genes/channels in blood pressure control.

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A G-quadruplex nanoswitch in the SGK1 promoter regulates isoform expression by K+/Na+ balance and resveratrol binding

Cited by 7 publications

References 44 publications

Resveratrol targets G-quadruplexes to exert its pharmacological effects

Resveratrol targets G-quadruplexes to exert its pharmacological effects

Glucocorticoids ameliorate cardiorenal syndrome through the NPR1/SGK1 pathway in natriuretic peptide receptor A‑heterozygous mice

Kidney ion handling genes and their interaction in blood pressure control

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