Abstract 113: Renal Phenotype of Inwardly Rectifying Potassium Channel Kcnj16 (Kir 5.1) Knockout in the Dahl Salt-Sensitive Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Oleg Palygin ◽  
Vladislav Levchenko ◽  
Daria V Ilatovskaya ◽  
Jessica L Barnett ◽  
Aron M Geurts ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Basolateral Membrane ◽  
Critical Role ◽  
Electrolyte Imbalance ◽  
Electrophysiological Recording ◽  
Resting Membrane Potential ◽  
Electrolyte Balance ◽  
Renal Tubules ◽  
Basolateral Membranes ◽  
Hypokalemic Alkalosis

The inward-rectifying channels play an important role in the control of resting membrane potential and tubular homeostasis in the kidney. Kcnj16 (Kir 5.1) form a heteromeric channel with Kcnj10 (Kir 4.1) at the basolateral membranes of aldosterone-sensitive distal nephron (ASDN); mutations in the human KCNJ10 gene result in SeSAME)/EAST syndrome, a complex disorder that includes salt wasting and hypokalemic alkalosis. To illuminate the importance of Kcnj16 (Kir 5.1) in the context of a disease state in vivo, we generated a Kcnj16 knockout rat model in Dahl salt-sensitive (SS) background by using ZFN technology. ZFN against Kcnj16 caused a 18-bp in-frame deletion that occurred in the second protein transmembrane domain. IHC analysis demonstrated highly specific expression of Kcnj16 on the basolateral membranes of ASDN in the control kidneys of SS rats, which was completely abolished in Kcnj16-/- rats. The electrophysiological recording of K+ channels in the CCD basolateral membrane revealed activity of only homomeric Kcnj10 channels (21 pS channel in Kcnj16-/- rats compared to both 41 and 21 pS channels in SS rats). Thus, these data provide evidence of successful knock out of this protein and consequent degradation of the channel in renal tubules. The Kcnj16-/- knockout in SS rat induces electrolyte imbalance, epileptic seizures and result in changes in development (37% reduction in body and 54% in kidney mass). The mean arterial pressure was significantly lower in Kcnj16-/- compared to SS rats (91.3±1.8 to 104.7±5.5 mmHg) when animals were fed a low salt (0.4%) diet. Knockout of Kcnj16 resulted in hypokalemia (4.25±0.09 vs 2.08±0.12 mmol/L in serum of control vs KO rats), hypermagnesemia (0.49±0.02 vs 0.63±0.01 mmol/L in serum of control vs KO rats), and FSGS. Urea electrolyte balance was also disturbed compared to control animals. Importantly, change of the diet to high salt (4%) caused mortality of KO rats within 1-2 days. These data demonstrate critical role of Kcnj16 channels in renal salt handling and in the development of salt-sensitive hypertension.

scholarly journals A CD317/tetherin–RICH2 complex plays a critical role in the organization of the subapical actin cytoskeleton in polarized epithelial cells

2009 ◽  
Vol 184 (5) ◽  
pp. 721-736 ◽  
Author(s):  
Ruth Rollason ◽  
Viktor Korolchuk ◽  
Clare Hamilton ◽  
Mark Jepson ◽  
George Banting
Keyword(s):  
Epithelial Cells ◽  
Actin Cytoskeleton ◽  
Transmembrane Domain ◽  
Basolateral Membrane ◽  
Critical Role ◽  
Integral Membrane Protein ◽  
Apical Surface ◽  
Actin Network ◽  
Cell Height ◽  
Polarized Epithelial Cells

CD317/tetherin is a lipid raft–associated integral membrane protein with a novel topology. It has a short N-terminal cytosolic domain, a conventional transmembrane domain, and a C-terminal glycosyl-phosphatidylinositol anchor. We now show that CD317 is expressed at the apical surface of polarized epithelial cells, where it interacts indirectly with the underlying actin cytoskeleton. CD317 is linked to the apical actin network via the proteins RICH2, EBP50, and ezrin. Knocking down expression of either CD317 or RICH2 gives rise to the same phenotype: a loss of the apical actin network with concomitant loss of apical microvilli, an increase in actin bundles at the basal surface, and a reduction in cell height without any loss of tight junctions, transepithelial resistance, or the polarized targeting of apical and basolateral membrane proteins. Thus, CD317 provides a physical link between lipid rafts and the apical actin network in polarized epithelial cells and is crucial for the maintenance of microvilli in such cells.

Subcellular distribution of nucleotide cyclases in rat intestinal epithelium.

1978 ◽  
Vol 235 (5) ◽  
pp. E539 ◽  
Author(s):  
M W Walling ◽  
A K Mircheff ◽  
C H Van Os ◽  
E M Wright
Keyword(s):  
Adenylate Cyclase ◽  
Guanylate Cyclase ◽  
Brush Border ◽  
Linear Regression Analysis ◽  
Basolateral Membrane ◽  
Multiple Linear Regression Analysis ◽  
Isolated Cells ◽  
Basolateral Membranes ◽  
Rat Duodenum ◽  
Triton X

The subcellular distributions of adenylate cyclase and guanylate cyclase were determined for the mature enterocyte from the rat duodenum. Brush-border and basolateral membranes were prepared from isolated cells by an analytical isolation procedure, and multiple linear regression analysis was used to obtain a quantitative estimate of the distribution of recovered cyclase activities between the brush borders and basolateral membranes. Adenylate cyclase was largely confined to the basolateral surface of the epithelium, whereas guanylate cyclase was found on the brush-border and basolateral membrane fractions in the ratio 2.4:1. There was no evidence for the presence of nucleotide cyclases in the cytosol. Guanylate cyclase in both the brush-border and basolateral membranes was stimulated by epinephrine, insulin, and Triton X-100, but not by carbachol. Adenylate cyclase was not influenced by epinephrine, but was markedly stimulated by NaF and vasoactive intestinal peptide. These results are discussed in relation to the effects of hormones on transport across the small intestine.

scholarly journals GANGGUAN KESEIMBANGAN AIR DAN NATRIUM SERTA PEMERIKSAAN OSMOLALITAS

2014 ◽  
Vol 6 (3) ◽  
Author(s):  
Glady I. Rambert
Keyword(s):  
Antidiuretic Hormone ◽  
Water Distribution ◽  
Freezing Point ◽  
Urine Osmolality ◽  
Body Fluids ◽  
The State ◽  
The Body ◽  
Electrolyte Imbalance ◽  
Electrolyte Balance ◽  
Freezing Point Depression

Abstract: Water distribution in each compartment of the body involves concentration of solutes in body fluids, and the amount of dissolved substance in a solvent called osmolality. Electrolyte that has the biggest contributor in determining the serum osmolality is sodium, which is osmotically active. Hipoosmolality actually describes the state of hyponatremia, and hyperosmolality describes the state of hypernatremia. Examination of plasma and urine osmolality is very helpful in the management of patients with water and electrolyte imbalance, in addition to assess the antidiuretic hormone (ADH) abnormalities. Urine osmolality is important in evaluating the ability of the kidney to concentrate the urine, in addition to monitor the fluid and electrolyte balance. There are two ways of osmolality examination: 1) indirectly, by using osmometer (osmolality measurement) with a freezing point depression method; 2) directly, by using a formula (osmolality count).Keywords: water, sodium, osmolality, freezing point depression, osmolality countAbstrak: Distribusi air pada setiap kompartemen tubuh melibatkan kadar zat terlarut di dalam cairan tubuh, dan jumlah zat terlarut dalam suatu pelarut yang disebut osmolalitas. Elektrolit pemberi kontribusi terbesar dalam menentukan besarnya osmolalitas serum ialah natrium, yang aktif secara osmotik. Keadaan hipoosmolalitas sebenarnya menggambarkan keadaan hiponatremia, sebaliknya hiperosmolalitas menggambarkan keadaan hipernatremia. Pemeriksaan osmolalitas plasma dan urin sangat membantu penatalaksanaan pasien dengan gangguan keseimbangan air dan elektrolit, selain menilai kelainan antidiuretic hormone (ADH). Osmolalitas urin penting untuk mengetahui kemampuan ginjal memekatkan urin, selain memonitor keseimbangan cairan dan elektrolit. Terdapat dua cara pemeriksaan osmolalitas yaitu: 1) secara tidak langsung menggunakan osmometer (osmolalitas ukur) dengan metode freezing point depression; 2) secara langsung dengan menggunakan rumus (osmolalitas hitung).Kata kunci: air, natrium, osmolalitas, freezing point depression, osmolalitas hitung

scholarly journals Mathematical modeling of ischemic stroke

2019 ◽  
Vol 11 (4) ◽  
pp. 38-43
Author(s):  
V. I. Ershov ◽  
A. N. Chirkov ◽  
A. P. Gonchar-Zaykin ◽  
S. N. Lyashchenko ◽  
T. Yu. Lozinskaya ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Mortality Rate ◽  
Diabetes Insipidus ◽  
Prognostic Value ◽  
Hormone Secretion ◽  
Fatal Outcome ◽  
Electrolyte Imbalance ◽  
Electrolyte Balance ◽  
Plasma Osmolarity ◽  
The Impact

Objective: to determine the prognostic value of the indicators of fluid and electrolyte balance in the acutest period of severe ischemic stroke (IS). Patients and methods. A total of 150 patients with severe IS of various locations and pathogenetic subtypes were examined. The impact of plasma osmolarity or sodium levels on the course and prognosis of IS was studied on day 1 of the disease. Results and discussion. It has been established that in patients with severe IS, the most common type of fluid and electrolyte imbalance is hyperosmolar hypernatremic syndrome that develops at the onset of severe IS, serves as a factor for poor outcome, and is accompanied by high mortality. The rate of fatal outcomes in hypoosmolar syndromes is higher than that in normal plasma osmolarity, but significantly lower than that in hyperosmolar syndromes. Cerebral salt wasting (CSW) is associated with a higher mortality rate than syndrome of inappropriate antidiuretic hormone secretion (SIADH), which confirms a worse prognostic value in hypovolemia than in normo- and hypervolemia. The development of diabetes insipidus at the onset of IS reflects the degree of brainstem structural destruction and, accordingly, is associated with the highest rate of fatal outcomes. The cardioembolic pathogenetic subtype of IS is characterized by a more severe course and a higher probable mortality rate in both hypoosmolar and normosmolar conditions.Conclusion. Impaired fluid and electrolyte homeostasis is of significant prognostic value for the outcome of IS. In this case, the leading role is played by the hyperosmolar hypernatremic syndrome, in which the probability of a fatal outcome is highest and there is a need for continuous patient health monitoring and high-speed decision-making aimed to correct this condition. Therapeutic policy for diabetes insipidus depends on the duration of IS. The risk for fatal outcome in the cardioembolic pathogenetic subtype of IS is higher than that in atherothrombotic stroke, at any plasma osmolarity and sodium levels.

scholarly journals Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3314
Author(s):  
Kun Fang ◽  
Dong Liu ◽  
Salil S. Pathak ◽  
Bowen Yang ◽  
Jin Li ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Translational Control ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Mapk Signaling ◽  
Repetitive Behaviors ◽  
Behavioral Changes ◽  
Circadian Disruption ◽  
Electrophysiological Recording ◽  
Functional Changes

Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment.

scholarly journals Putative linear motifs mediate the trafficking to apical and basolateral membranes

2020 ◽  
Author(s):  
Laszlo Dobson ◽  
András Zeke ◽  
Levente Szekeres ◽  
Tamás Langó ◽  
Gábor Tusnády
Keyword(s):  
Epithelial Cells ◽  
Drug Transport ◽  
Basolateral Membrane ◽  
Transmembrane Proteins ◽  
Transport Processes ◽  
Membrane Domains ◽  
Protein Distribution ◽  
Basolateral Membranes ◽  
Linear Motifs ◽  
Cellular Components

AbstractCell polarity refers to the asymmetric organisation of cellular components in various cells. Epithelial cells are the best known examples of polarized cells, featuring apical and basolateral membrane domains. Despite huge efforts, the exact rules governing the protein distribution in such domains are still elusive. In this study we examined linear motifs accumulating in these parts and based on the results we prepared ‘Classical’ and Convolutional Neural Networks to classify human transmembrane proteins localizing into apical/basolateral membranes. Asymmetric expression of drug transporters results in vectorial drug transport, governing the pharmacokinetics of numerous substances, yet the data on how proteins are sorted in epithelial cells is very scattered. The provided dataset may offer help to experimentalists to characterize novel molecular targets to regulate transport processes more precisely.

scholarly journals Identification of a putative binding site critical for general anesthetic activation of TRPA1

2017 ◽  
Vol 114 (14) ◽  
pp. 3762-3767 ◽  
Author(s):  
Hoai T. Ton ◽  
Thieu X. Phan ◽  
Ara M. Abramyan ◽  
Lei Shi ◽  
Gerard P. Ahern
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Halogen Bond ◽  
Critical Role ◽  
Sensory Nerves ◽  
Structural Basis ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Potential Binding

General anesthetics suppress CNS activity by modulating the function of membrane ion channels, in particular, by enhancing activity of GABAA receptors. In contrast, several volatile (isoflurane, desflurane) and i.v. (propofol) general anesthetics excite peripheral sensory nerves to cause pain and irritation upon administration. These noxious anesthetics activate transient receptor potential ankyrin repeat 1 (TRPA1), a major nociceptive ion channel, but the underlying mechanisms and site of action are unknown. Here we exploit the observation that pungent anesthetics activate mammalian but not Drosophila TRPA1. Analysis of chimeric Drosophila and mouse TRPA1 channels reveal a critical role for the fifth transmembrane domain (S5) in sensing anesthetics. Interestingly, we show that anesthetics share with the antagonist A-967079 a potential binding pocket lined by residues in the S5, S6, and the first pore helix; isoflurane competitively disrupts A-967079 antagonism, and introducing these mammalian TRPA1 residues into dTRPA1 recapitulates anesthetic agonism. Furthermore, molecular modeling predicts that isoflurane and propofol bind to this pocket by forming H-bond and halogen-bond interactions with Ser-876, Met-915, and Met-956. Mutagenizing Met-915 or Met-956 selectively abolishes activation by isoflurane and propofol without affecting actions of A-967079 or the agonist, menthol. Thus, our combined experimental and computational results reveal the potential binding mode of noxious general anesthetics at TRPA1. These data may provide a structural basis for designing drugs to counter the noxious and vasorelaxant properties of general anesthetics and may prove useful in understanding effects of anesthetics on related ion channels.

Disorders of Water and Sodium Balance: Hyponatremia

2019 ◽  
Author(s):  
Danilea M. Carmona Matos ◽  
Herbert Chen
Keyword(s):  
Antidiuretic Hormone ◽  
Sodium Transport ◽  
Clinical Manifestations ◽  
Electrolyte Imbalance ◽  
Renal Physiology ◽  
Sodium Balance ◽  
Electrolyte Balance ◽  
Clear Understanding ◽  
Drug Induced ◽  
Clinical Scenarios

Disorders of water and sodium balance are common in clinical practice. To better assess them, we must have a clear understanding of water-electrolyte homeostasis and renal function. The following review goes over practical equations necessary for electrolyte balance analysis as well as the foundations of renal physiology. Emphasis is placed on the understanding of sodium transport and its physiologic and pharmacologic regulation. In addition, we explore the most common electrolyte imbalance affecting up to 28% of hospitalized patients: hyponatremia (ie, low sodium concentration). Hyponatremia has been found in several acute and chronic clinical scenarios including postoperative, drug-induced, and exercise-associated hyponatremia. However, it is not uncommon to find this disorder coexisting with other diseases such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acquired immunodeficiency syndrome (AIDS), cancer, and in rare cases, hypothyroidism. To better understand this disorder, the etiology, diagnosis with clinical manifestations and laboratory values, and treatment options are explored. This review contains 9 figures, 6 tables, and 52 references. Key Words: aldosterone, antidiuretic hormone, body fluids, electrolyte balance, hyponatremia, hypovolemia, osmolality, sodium transport, vasopressin

Disorders of Water and Sodium Balance: Hyponatremia

2019 ◽  
Author(s):  
Danilea M. Carmona Matos ◽  
Herbert Chen
Keyword(s):  
Antidiuretic Hormone ◽  
Sodium Transport ◽  
Clinical Manifestations ◽  
Electrolyte Imbalance ◽  
Renal Physiology ◽  
Sodium Balance ◽  
Electrolyte Balance ◽  
Clear Understanding ◽  
Drug Induced ◽  
Clinical Scenarios

Disorders of water and sodium balance are common in clinical practice. To better assess them, we must have a clear understanding of water-electrolyte homeostasis and renal function. The following review goes over practical equations necessary for electrolyte balance analysis as well as the foundations of renal physiology. Emphasis is placed on the understanding of sodium transport and its physiologic and pharmacologic regulation. In addition, we explore the most common electrolyte imbalance affecting up to 28% of hospitalized patients: hyponatremia (ie, low sodium concentration). Hyponatremia has been found in several acute and chronic clinical scenarios including postoperative, drug-induced, and exercise-associated hyponatremia. However, it is not uncommon to find this disorder coexisting with other diseases such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acquired immunodeficiency syndrome (AIDS), cancer, and in rare cases, hypothyroidism. To better understand this disorder, the etiology, diagnosis with clinical manifestations and laboratory values, and treatment options are explored. This review contains 9 figures, 6 tables, and 52 references. Key Words: aldosterone, antidiuretic hormone, body fluids, electrolyte balance, hyponatremia, hypovolemia, osmolality, sodium transport, vasopressin

Disorders of Water and Sodium Balance: Hyponatremia

2019 ◽  
Author(s):  
Danilea M. Carmona Matos ◽  
Herbert Chen
Keyword(s):  
Antidiuretic Hormone ◽  
Sodium Transport ◽  
Clinical Manifestations ◽  
Electrolyte Imbalance ◽  
Renal Physiology ◽  
Sodium Balance ◽  
Electrolyte Balance ◽  
Clear Understanding ◽  
Drug Induced ◽  
Clinical Scenarios

Disorders of water and sodium balance are common in clinical practice. To better assess them, we must have a clear understanding of water-electrolyte homeostasis and renal function. The following review goes over practical equations necessary for electrolyte balance analysis as well as the foundations of renal physiology. Emphasis is placed on the understanding of sodium transport and its physiologic and pharmacologic regulation. In addition, we explore the most common electrolyte imbalance affecting up to 28% of hospitalized patients: hyponatremia (ie, low sodium concentration). Hyponatremia has been found in several acute and chronic clinical scenarios including postoperative, drug-induced, and exercise-associated hyponatremia. However, it is not uncommon to find this disorder coexisting with other diseases such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acquired immunodeficiency syndrome (AIDS), cancer, and in rare cases, hypothyroidism. To better understand this disorder, the etiology, diagnosis with clinical manifestations and laboratory values, and treatment options are explored. This review contains 9 figures, 6 tables, and 52 references. Key Words: aldosterone, antidiuretic hormone, body fluids, electrolyte balance, hyponatremia, hypovolemia, osmolality, sodium transport, vasopressin

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