OBJECTIVETo review the recent developments in the mechanisms of epithelium sodium channels (ENaCs) induced bone formation and regulation.

DATA SOURCESStudies written in English or Chinese were searched using Medline, PubMed and the index of Chinese-language literature with time restriction from 2005 to 2014. Keywords included ENaC, bone, bone formation, osteonecrosis, estrogen, and osteoporosis. Data from published articles about the structure of ENaC, mechanism of ENaC in bone formation in recent domestic and foreign literature were selected.

STUDY SELECTIONAbstract and full text of all studies were required to obtain. Studies those were not accessible and those did not focus on the keywords were excluded.

RESULTSENaCs are tripolymer ion channels which are assembled from homologous α, β, and γ subunits. Crystal structure of ENaCs suggests that ENaC has a central ion-channel located in the central symmetry axis of the three subunits. ENaCs are protease sensitive channels whose iron-channel activity is regulated by the proteolytic reaction. Channel opening probability of ENaCs is regulated by proteinases, mechanical force, and shear stress. Several molecules are involved in regulation of ENaCs in bone formation, including nitride oxide synthases, voltage-sensitive calcium channels, and cyclooxygenase-2.

CONCLUSIONThe pathway of ENaC involved in shear stress has an effect on stimulating osteoblasts even bone formation by estrogen interference.

Calcium Channels ; physiology ; Epithelial Sodium Channels ; chemistry ; physiology ; Estrogens ; pharmacology ; Humans ; Osteogenesis ; physiology

Renal outer medullary potassium (ROMK) channel is an important K⁺ excretion channel in the body, and K⁺ secreted by the ROMK channels is most or all source of urinary potassium. Previous studies focused on the ROMK channels of thick ascending limb (TAL) and collecting duct (CD), while there were few studies on the involvement of ROMK channels of the late distal convoluted tubule (DCT2) in K⁺ excretion. The purpose of the present study was mainly to record the ROMK channels current in renal DCT2 and observe the effect of high potassium diet on the ROMK channels by using single channel and whole-cell patch-clamp techniques. The results showed that a small conductance channel current with a conductance of 39 pS could be recorded in the apical membrane of renal DCT2, and it could be blocked by Tertiapin-Q (TPNQ), a ROMK channel inhibitor. The high potassium diet significantly increased the probability of ROMK channel current occurrence in the apical membrane of renal DCT2, and enhanced the activity of ROMK channel, compared to normal potassium diet (P < 0.01). Western blot results also demonstrated that the high potassium diet significantly up-regulated the protein expression levels of ROMK channels and epithelial sodium channel (ENaC), and down-regulated the protein expression level of Na⁺-Cl^- cotransporter (NCC). Moreover, the high potassium diet significantly increased urinary potassium excretion. These results suggest that the high potassium diet may activate the ROMK channels in the apical membrane of renal DCT2 and increase the urinary potassium excretion by up-regulating the expression of renal ROMK channels.
Potassium Channels, Inwardly Rectifying/metabolism* ; Kidney Tubules, Distal/metabolism* ; Potassium/metabolism* ; Epithelial Sodium Channels/metabolism* ; Diet

The present study was aimed to explore the role of sympathetic and parasympathetic nerves in the regulation of sodium transporters and water channels in the salivary gland. Rats were denervated of their sympathetic and parasympathetic nerves to the submandibular gland, and the glandular expression of sodium transporters and water channels was determined by Western blot analysis. The expression of either alpha1 or beta1 subunit of Na, K-ATPase was not significantly affected either by the sympathetic or by the parasympathetic denervation. The expression of subunits of epithelial sodium channels was significantly increased both in the denervated and contralateral glands either by the sympathetic or by the parasympathetic denervation. Neither the sympathetic nor the parasympathetic denervation significantly altered the expression of aquaporin-1 (AQP1). Nor was the expression of AQP4 affected significantly by the parasympathetic or the sympathetic denervation. On the contrary, the expression of AQP5 was significantly increased not only by the parasympathetic but also by the sympathetic denervation. These results suggest that sympathetic and parasympathetic nerves have tonic regulatory effects on the regulation of certain sodium transporters and AQP water channels in the salivary gland.
Animals ; Aquaporins* ; Blotting, Western ; Epithelial Sodium Channels ; Parasympathectomy ; Rats* ; Salivary Glands ; Sodium* ; Submandibular Gland* ; Sympathectomy

The present study was undertaken to explore the role of autonomic nerves in the regulation of sodium transporters and water channels in the salivary gland. Rats were denervated of their sympathetic or parasympathetic nerves to the submandibular gland. One week later, the expression of Na,K-ATPase, epithelial sodium channels (ENaC), and aquaporins (AQP) was examined in the denervated and contralateral glands. The sympathetic denervation slightly but significantly decreased the expression of alpha1 subunit of Na,K-ATPase, whereas the parasympathetic denervation increased it. The expression of alpha-subunit of ENaC was significantly increased in both the denervated and contralateral glands either by the sympathetic or parasympathetic denervation. The sympathetic denervation significantly increased the expression of AQP5 in both the denervated and contralateral glands, whereas the parasympathetic denervation decreased it. It is suggested that the autonomic nerves have a tonic effect on the regulation of sodium transporters and AQP water channels in the salivary gland.
Animals ; Aquaporins* ; Autonomic Pathways ; Epithelial Sodium Channels ; Parasympathectomy ; Rats* ; Salivary Glands ; Sodium* ; Submandibular Gland* ; Sympathectomy

Cells can resist and even recover from stress induced by acute hypoxia, whereas chronic hypoxia often leads to irreversible damage and eventually death. Although little is known about the response(s) to acute hypoxia in neuronal cells, alterations in ion channel activity could be preferential. This study aimed to elucidate which channel type is involved in the response to acute hypoxia in rat pheochromocytomal (PC12) cells as a neuronal cell model. Using perfusing solution saturated with 95% N2 and 5% CO2, induction of cell hypoxia was confirmed based on increased intracellular Ca2+ with diminished oxygen content in the perfusate. During acute hypoxia, one channel type with a conductance of about 30 pS (2.5 pA at -80 mV) was activated within the first 2~3 min following onset of hypoxia and was long-lived for more than 300 ms with high open probability (Po, up to 0.8). This channel was permeable to Na+ ions, but not to K+, Ca+, and Cl- ions, and was sensitively blocked by amiloride (200 nM). These characteristics and behaviors were quite similar to those of epithelial sodium channel (ENaC). RT-PCR and Western blot analyses confirmed that ENaC channel was endogenously expressed in PC12 cells. Taken together, a 30-pS ENaC-like channel was activated in response to acute hypoxia in PC12 cells. This is the first evidence of an acute hypoxia-activated Na+ channel that can contribute to depolarization of the cell.
Amiloride ; Animals ; Anoxia ; Blotting, Western ; Cell Hypoxia ; Epithelial Sodium Channels ; Ion Channels ; Ions ; Neurons ; Oxygen ; PC12 Cells ; Pheochromocytoma ; Rats

OBJECTIVETo investigate the distribution and role of alpha, beta and gamma subunits of epithelial sodium channel (ENaC) in the cochlea and endolymphatic sac of guinea pig.

METHODSThe expression of alpha-, beta- and gamma-ENaC subunits proteins was studied by immunohistochemistry with the specific polyclonal rabbit antibodies against the alpha, beta and gamma subunits of rat ENaC. Alpha-ENaC mRNA was detected by in situ hybridization with digoxin labeled cDNA probe.

RESULTSAll three subunits of ENaC, alpha-, beta- and gamma-, were widely distributed in the labyrinth. In the cochlea, strong labeling of alpha-ENaC protein was found in the spiral limbus, and to a less extent, in the spiral ligament, organ of Corti and Reissner's membrane. The immunoreactivity of beta-ENaC was observed in the spiral ligament, spiral limbus, spiral ganglion, organ of Corti and Reissner's membrane with a less intensity than that of alpha-ENaC. Gamma-ENaC was presented primarily in the superior part of the spiral ligament, spiral limbus, spiral ganglion, and weakly in the organ of Corti and Reissner's membrane. In the endolymphatic sac, intensive immunoreactivities of all three subunits were seen in the epithelial cells and the subepithelial cells at similar intensity. Alpha-ENaC mRNA was localized in the spiral limbus, the inferior part of spiral ligament, stria vascularis, and epithelial cells and subepithelial cells of endolymphatic sac.

CONCLUSIONDifferent subunits of the ENaC expressed in various cell regions of the cochlea and endolymphatic sac in distinct patterns may form the functional sodium channel to regulate the endolymph, thus serve to maintain homeostasis in inner ear.

Animals ; Cochlea ; metabolism ; Endolymphatic Sac ; metabolism ; Epithelial Sodium Channels ; metabolism ; Guinea Pigs

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction, which causes most CF morbidity and mortality. This article reviews the pathophysiology of CF, recent animal models, and current treatment of CF.
Airway Obstruction ; Chloride Channels ; Cystic Fibrosis Transmembrane Conductance Regulator ; Cystic Fibrosis ; Epithelial Cells ; Epithelial Sodium Channels ; Half-Life ; Inflammation ; Intestines ; Lung Diseases ; Lung ; Membranes ; Models, Animal ; Mortality ; Pancreas

Hyponatremia and hyperkalemia in infancy can be attributed to various causes, originating from a variety of renal and genetic disorders. Pseudohypoaldosteronism type 1 (PHA1) is one of these disorders, causing mineralocorticoid resistance that results in urinary salt wasting, failure to thrive, metabolic acidosis, and dehydration. PHA1 is heterogeneous in etiology. Inactivating mutations in the NR3C2 gene (4q31.1), which encodes the mineralocorticoid receptor, causes a less severe autosomal dominant form that is restricted to the kidney, while mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects. Here we report a neonatal case of kidney restricted PHA1 (renal type of PHA1) who first showed laboratory abnormalities before obvious PHA1 manifestations, with two functional polymorphisms in the NR3C2 gene. This is the second genetically confirmed case in Korea and the first to show functional polymorphisms that have previously been reported in the literature.
Acidosis ; Dehydration ; Epithelial Sodium Channels ; Failure to Thrive ; Humans ; Hyperkalemia ; Hyponatremia ; Infant, Newborn* ; Kidney ; Korea ; Male* ; Pseudohypoaldosteronism* ; Receptors, Mineralocorticoid*

Type B and non-A, non-B intercalated cells are found within the connecting tubule and the cortical collecting duct. Of these cell types, type B intercalated cells are known to mediate Cl⁻ absorption and HCO₃⁻ secretion largely through pendrin-dependent Cl⁻/HCO₃⁻ exchange. This exchange is stimulated by angiotensin II administration and is also stimulated in models of metabolic alkalosis, for instance after aldosterone or NaHCO₃ administration. In some rodent models, pendrin-mediated HCO₃⁻ secretion modulates acid-base balance. However, the role of pendrin in blood pressure regulation is likely of more physiological or clinical significance. Pendrin regulates blood pressure not only by mediating aldosterone-sensitive Cl⁻ absorption, but also by modulating the aldosterone response for epithelial Na⁺ channel (ENaC)-mediated Na⁺ absorption. Pendrin regulates ENaC through changes in open channel of probability, channel surface density, and channels subunit total protein abundance. Thus, aldosterone stimulates ENaC activity through both direct and indirect effects, the latter occurring through its stimulation of pendrin expression and function. Therefore, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contributory role of pendrin in distal nephron function and blood pressure.
Absorption ; Acid-Base Equilibrium ; Adrenal Medulla ; Aldosterone ; Alkalosis ; Angiotensin II ; Angiotensins ; Blood Pressure* ; Catecholamines ; Epithelial Sodium Channels ; Negotiating ; Nephrons ; Rodentia

Type B and non-A, non-B intercalated cells are found within the connecting tubule and the cortical collecting duct. Of these cell types, type B intercalated cells are known to mediate Cl⁻ absorption and HCO₃⁻ secretion largely through pendrin-dependent Cl⁻/HCO₃⁻ exchange. This exchange is stimulated by angiotensin II administration and is also stimulated in models of metabolic alkalosis, for instance after aldosterone or NaHCO₃ administration. In some rodent models, pendrin-mediated HCO₃⁻ secretion modulates acid-base balance. However, the role of pendrin in blood pressure regulation is likely of more physiological or clinical significance. Pendrin regulates blood pressure not only by mediating aldosterone-sensitive Cl⁻ absorption, but also by modulating the aldosterone response for epithelial Na⁺ channel (ENaC)-mediated Na⁺ absorption. Pendrin regulates ENaC through changes in open channel of probability, channel surface density, and channels subunit total protein abundance. Thus, aldosterone stimulates ENaC activity through both direct and indirect effects, the latter occurring through its stimulation of pendrin expression and function. Therefore, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contributory role of pendrin in distal nephron function and blood pressure.
Absorption ; Acid-Base Equilibrium ; Adrenal Medulla ; Aldosterone ; Alkalosis ; Angiotensin II ; Angiotensins ; Blood Pressure* ; Catecholamines ; Epithelial Sodium Channels ; Negotiating ; Nephrons ; Rodentia