ENaC in Salt-Sensitive Hypertension: Kidney and Beyond

Pitzer, Ashley; Beusecum, Justin P Van; Kleyman, Thomas R.; Kirabo, Annet

doi:10.1007/s11906-020-01067-9

Cited by 60 publications

(55 citation statements)

References 147 publications

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“…Recently, Lee et al, in our laboratory, reported that PDC activity and expression are increased in both renal proximal tubule cells and cortical homogenates from spontaneously hypertensive rats compared with normotensive Wistar-Kyoto rats ( Lee et al, 2014 ). This activation may be involved in the increase in the expression of sodium transporters and channels in nephron segments, including the renal proximal tubule ( Knepper and Brooks, 2001 ; Wang et al, 2009 ; Maxwell et al, 2020 ; Pitzer et al, 2020 ).…”

Section: Renal Dysfunction In Metabolic Syndromementioning

confidence: 99%

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction

Lee

José

2021

Front. Pharmacol.

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Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity (increased waist circumference), hyperglycemia, dyslipidemia (high triglyceride blood levels, low high-density lipoprotein blood levels), and increased blood pressure. Oxidative stress, caused by the imbalance between pro-oxidant and endogenous antioxidant systems, is the primary pathological basis of MetS. The major sources of reactive oxygen species (ROS) associated with MetS are nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases and mitochondria. In this review, we summarize the current knowledge regarding the generation of ROS from NADPH oxidases and mitochondria, discuss the NADPH oxidase- and mitochondria-derived ROS signaling and pathophysiological effects, and the interplay between these two major sources of ROS, which leads to chronic inflammation, adipocyte proliferation, insulin resistance, and other metabolic abnormalities. The mechanisms linking MetS and chronic kidney disease are not well known. The role of NADPH oxidases and mitochondria in renal injury in the setting of MetS, particularly the influence of the pyruvate dehydrogenase complex in oxidative stress, inflammation, and subsequent renal injury, is highlighted. Understanding the molecular mechanism(s) underlying MetS may lead to novel therapeutic approaches by targeting the pyruvate dehydrogenase complex in MetS and prevent its sequelae of chronic cardiovascular and renal diseases.

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Section: Renal Dysfunction In Metabolic Syndromementioning

confidence: 99%

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction

Lee

José

2021

Front. Pharmacol.

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“…The hypothesis proposes that sodium can enter to APCs via epithelial sodium channel (ENaC) leading to intracellular formation of IsoLGs, in a process regulated by the Serum and Glucocorticoid Kinase-1 (SGK1) and by NADPH oxidase [23,32]. This mechanism is quite interesting because suggest a new role for ENaC inhibition in the therapy for AH [33].…”

Section: Sodium Effect On Immune Cells In Hypertensionmentioning

confidence: 99%

Is the Sodium an Activator of Immune System in Hypertension?

Amador

2021

BJSTR

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The sodium plays an essential role in human homeostasis and it has been described that a 30-50% of hypertensive patients are sensible to changes in their blood pressure after dietary high sodium intake. The last 20 years have been very active in trying to answer how the immune cells participate in hypertension, where the implications of increased sodium salt intake on the activation of the immune system have not been fully clarified. Even when some described mechanisms for macrophages, dendritic cells and lymphocytes proportion great insight for this understanding, the information concerning the different sodium compartments for its storage arise a new challenge for this area. This mini review highlights recent studies in different experimental settings regarding the effect of sodium as an activator for the immune system in hypertension and the mechanisms involved. We comment also the last studies suggesting the role of sodium as a regulator of immune cells in kidney medulla and extrarenal compartments that possibly may be involved in hypertension.

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“…ENaC serves as one of several key final effectors of the renin-AngII-aldosterone system during regulation of blood pressure 8 . Abnormalities in ENaC function have been directly linked to several human diseases of blood pressure including the hypertensive state of Liddle’s syndrome and the hypotensive state of pseudohypoaldosteronism type I 5 , 6 , 9 .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms and consequences of casein kinase II and ankyrin-3 regulation of the epithelial Na+ channel

El-Aziz

Soares

Mironova

et al. 2021

Sci Rep

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Activity of the Epithelial Na+ Channel (ENaC) in the distal nephron fine-tunes renal sodium excretion. Appropriate sodium excretion is a key factor in the regulation of blood pressure. Consequently, abnormalities in ENaC function can cause hypertension. Casein Kinase II (CKII) phosphorylates ENaC. The CKII phosphorylation site in ENaC resides within a canonical “anchor” ankyrin binding motif. CKII-dependent phosphorylation of ENaC is necessary and sufficient to increase channel activity and is thought to influence channel trafficking in a manner that increases activity. We test here the hypothesis that phosphorylation of ENaC by CKII within an anchor motif is necessary for ankyrin-3 (Ank-3) regulation of the channel, which is required for normal channel locale and function, and the proper regulation of renal sodium excretion. This was addressed using a fluorescence imaging strategy combining total internal reflection fluorescence (TIRF) microscopy with fluorescence recovery after photobleaching (FRAP) to quantify ENaC expression in the plasma membrane in living cells; and electrophysiology to quantify ENaC activity in split-open collecting ducts from principal cell-specific Ank-3 knockout mice. Sodium excretion studies also were performed in parallel in this knockout mouse. In addition, we substituted a key serine residue in the consensus CKII site in β-ENaC with alanine to abrogate phosphorylation and disrupt the anchor motif. Findings show that disrupting CKII signaling decreases ENaC activity by decreasing expression in the plasma membrane. In the principal cell-specific Ank-3 KO mouse, ENaC activity and sodium excretion were significantly decreased and increased, respectively. These results are consistent with CKII phosphorylation of ENaC functioning as a “switch” that favors Ank-3 binding to increase channel activity.

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ENaC in Salt-Sensitive Hypertension: Kidney and Beyond

Cited by 60 publications

References 147 publications

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction

Is the Sodium an Activator of Immune System in Hypertension?

Mechanisms and consequences of casein kinase II and ankyrin-3 regulation of the epithelial Na+ channel

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