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Advances in Therapy Feb 2021Renal tubular acidosis (RTA) occurs when the kidneys are unable to maintain normal acid-base homeostasis because of tubular defects in acid excretion or bicarbonate ion... (Review)
Review
Renal tubular acidosis (RTA) occurs when the kidneys are unable to maintain normal acid-base homeostasis because of tubular defects in acid excretion or bicarbonate ion reabsorption. Using illustrative clinical cases, this review describes the main types of RTA observed in clinical practice and provides an overview of their diagnosis and treatment. The three major forms of RTA are distal RTA (type 1; characterized by impaired acid excretion), proximal RTA (type 2; caused by defects in reabsorption of filtered bicarbonate), and hyperkalemic RTA (type 4; caused by abnormal excretion of acid and potassium in the collecting duct). Type 3 RTA is a rare form of the disease with features of both distal and proximal RTA. Accurate diagnosis of RTA plays an important role in optimal patient management. The diagnosis of distal versus proximal RTA involves assessment of urinary acid and bicarbonate secretion, while in hyperkalemic RTA, selective aldosterone deficiency or resistance to its effects is confirmed after exclusion of other causes of hyperkalemia. Treatment options include alkali therapy in patients with distal or proximal RTA and lowering of serum potassium concentrations through dietary modification and potential new pharmacotherapies in patients with hyperkalemic RTA including newer potassium binders.
Topics: Acidosis, Renal Tubular; Bicarbonates; Humans; Hyperkalemia; Kidney; Potassium
PubMed: 33367987
DOI: 10.1007/s12325-020-01587-5 -
Chemico-biological Interactions Nov 2022In total, twenty elements appear to be essential for the correct functioning of the human body, half of which are metals and half are non-metals. Among those metals that... (Review)
Review
In total, twenty elements appear to be essential for the correct functioning of the human body, half of which are metals and half are non-metals. Among those metals that are currently considered to be essential for normal biological functioning are four main group elements, sodium (Na), potassium (K), magnesium (Mg), and calcium (Ca), and six d-block transition metal elements, manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn) and molybdenum (Mo). Cells have developed various metallo-regulatory mechanisms for maintaining a necessary homeostasis of metal-ions for diverse cellular processes, most importantly in the central nervous system. Since redox active transition metals (for example Fe and Cu) may participate in electron transfer reactions, their homeostasis must be carefully controlled. The catalytic behaviour of redox metals which have escaped control, e.g. via the Fenton reaction, results in the formation of reactive hydroxyl radicals, which may cause damage to DNA, proteins and membranes. Transition metals are integral parts of the active centers of numerous enzymes (e.g. Cu,Zn-SOD, Mn-SOD, Catalase) which catalyze chemical reactions at physiologically compatible rates. Either a deficiency, or an excess of essential metals may result in various disease states arising in an organism. Some typical ailments that are characterized by a disturbed homeostasis of redox active metals include neurological disorders (Alzheimer's, Parkinson's and Huntington's disorders), mental health problems, cardiovascular diseases, cancer, and diabetes. To comprehend more deeply the mechanisms by which essential metals, acting either alone or in combination, and/or through their interaction with non-essential metals (e.g. chromium) function in biological systems will require the application of a broader, more interdisciplinary approach than has mainly been used so far. It is clear that a stronger cooperation between bioinorganic chemists and biophysicists - who have already achieved great success in understanding the structure and role of metalloenzymes in living systems - with biologists, will access new avenues of research in the systems biology of metal ions. With this in mind, the present paper reviews selected chemical and biological aspects of metal ions and their possible interactions in living systems under normal and pathological conditions.
Topics: Calcium; Catalase; Chromium; Cobalt; Copper; Humans; Ions; Iron; Magnesium; Manganese; Metalloproteins; Molybdenum; Potassium; Sodium; Superoxide Dismutase; Zinc
PubMed: 36152810
DOI: 10.1016/j.cbi.2022.110173 -
Nutrients Jul 2016Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of... (Review)
Review
Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+) ATPase pump. Approximately 90% of potassium consumed (60-100 mEq) is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN) is the leading cause of cardiovascular disease (CVD) and a major financial burden ($50.6 billion) to the US public health system, and has a significant impact on all-cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics) may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dietary Supplements; Evidence-Based Medicine; Global Health; Glucose Intolerance; Humans; Hypertension; Intestinal Absorption; Kidney; Models, Biological; Potassium; Potassium Deficiency; Potassium, Dietary; Renal Elimination; Renal Reabsorption
PubMed: 27455317
DOI: 10.3390/nu8070444 -
International Journal of Molecular... Feb 2020Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important... (Review)
Review
Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important factor in CNS water and potassium homeostasis. Changes in AQP4 activity and expression have been implicated in several CNS disorders, including (but not limited to) epilepsy, edema, stroke, and glioblastoma. For this reason, many studies have been done to understand the various ways in which AQP4 is regulated endogenously, and could be regulated pharmaceutically. In particular, four regulatory methods have been thoroughly studied; regulation of gene expression via microRNAs, regulation of AQP4 channel gating/trafficking via phosphorylation, regulation of water permeability using heavy metal ions, and regulation of water permeability using small molecule inhibitors. A major challenge when studying AQP4 regulation is inter-method variability. A compound or phosphorylation which shows an inhibitory effect in vitro may show no effect in a different in vitro method, or even show an increase in AQP4 expression in vivo. Although a large amount of variability exists between in vitro methods, some microRNAs, heavy metal ions, and two small molecule inhibitors, acetazolamide and TGN-020, have shown promise in the field of AQP4 regulation.
Topics: Acetazolamide; Animals; Aquaporin 4; Central Nervous System; Central Nervous System Diseases; Homeostasis; Humans; Ions; Metals; MicroRNAs; Niacinamide; Permeability; Phosphorylation; Potassium; Proteolipids; Thiadiazoles; Water
PubMed: 32111087
DOI: 10.3390/ijms21051603 -
Current Biology : CB May 2021Metals are vital for life as they are necessary for essential biological processes. Traditionally, metals are categorized as either dynamic signals or static cofactors.... (Review)
Review
Metals are vital for life as they are necessary for essential biological processes. Traditionally, metals are categorized as either dynamic signals or static cofactors. Redox-inactive metals such as calcium (Ca), potassium (K), sodium (Na), and zinc (Zn) signal through large fluctuations in their metal-ion pools. In contrast, redox-active transition metals such as copper (Cu) and iron (Fe) drive catalysis and are largely characterized as static cofactors that must be buried and protected within the active sites of proteins, due to their ability to generate damaging reactive-oxygen species through Fenton chemistry. Cu has largely been studied as a static cofactor in fundamental processes from cellular respiration to pigmentation, working through cytochrome c oxidase and tyrosinase, respectively. However, within the last decade, a new paradigm in nutrient sensing and protein regulation - termed 'metalloallostery' - has emerged, expanding the repertoire of Cu beyond the catalytic proteins to dynamic signaling molecules essential for cellular processes that impact normal physiology and disease states. In this Primer we introduce both the 'traditional' and emerging roles for Cu in biology and the many ways in which Cu intersects with human health.
Topics: Animals; Calcium; Copper; Health; Humans; Ions; Iron; Potassium; Zinc
PubMed: 33974864
DOI: 10.1016/j.cub.2021.03.054 -
Nutrients Mar 2024Potassium is a monovalent cation widely present in nature, where it is not in metallic form, but always in combination with other substances, especially chloride [...].
Potassium is a monovalent cation widely present in nature, where it is not in metallic form, but always in combination with other substances, especially chloride [...].
Topics: Humans; Potassium; Chlorides; Potassium Chloride
PubMed: 38542744
DOI: 10.3390/nu16060833 -
Acta Crystallographica. Section D,... Apr 2020The study of ion channels dates back to the 1950s and the groundbreaking electrophysiology work of Hodgin and Huxley, who used giant squid axons to probe how action... (Review)
Review
The study of ion channels dates back to the 1950s and the groundbreaking electrophysiology work of Hodgin and Huxley, who used giant squid axons to probe how action potentials in neurons were initiated and propagated. More recently, several experiments using different structural biology techniques and approaches have been conducted to try to understand how potassium ions permeate through the selectivity filter of potassium ion channels. Two mechanisms of permeation have been proposed, and each of the two mechanisms is supported by different experiments. The key structural biology experiments conducted so far to try to understand how ion permeation takes place in potassium ion channels are reviewed and discussed. Protein crystallography has made, and continues to make, key contributions in this field, often through the use of anomalous scattering. Other structural biology techniques used to study the contents of the selectivity filter include solid-state nuclear magnetic resonance and two-dimensional infrared spectroscopy, both of which make clever use of isotopic labeling techniques, while molecular-dynamics simulations of ion flow through the selectivity filter have been enabled by the growing number of potassium ion channel structures deposited in the Protein Data Bank.
Topics: Crystallography, X-Ray; Isotope Labeling; Models, Molecular; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Potassium; Potassium Channels; Protein Structure, Tertiary; Scattering, Radiation; Spectrophotometry, Infrared
PubMed: 32254056
DOI: 10.1107/S2059798320003599 -
Science Translational Medicine Aug 2018Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia... (Randomized Controlled Trial)
Randomized Controlled Trial
Hyperphosphatemia is common in patients with chronic kidney disease and is increasingly associated with poor clinical outcomes. Current management of hyperphosphatemia with dietary restriction and oral phosphate binders often proves inadequate. Tenapanor, a minimally absorbed, small-molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), acts locally in the gastrointestinal tract to inhibit sodium absorption. Because tenapanor also reduces intestinal phosphate absorption, it may have potential as a therapy for hyperphosphatemia. We investigated the mechanism by which tenapanor reduces gastrointestinal phosphate uptake, using in vivo studies in rodents and translational experiments on human small intestinal stem cell-derived enteroid monolayers to model ion transport physiology. We found that tenapanor produces its effect by modulating tight junctions, which increases transepithelial electrical resistance (TEER) and reduces permeability to phosphate, reducing paracellular phosphate absorption. NHE3-deficient monolayers mimicked the phosphate phenotype of tenapanor treatment, and tenapanor did not affect TEER or phosphate flux in the absence of NHE3. Tenapanor also prevents active transcellular phosphate absorption compensation by decreasing the expression of NaPi2b, the major active intestinal phosphate transporter. In healthy human volunteers, tenapanor (15 mg, given twice daily for 4 days) increased stool phosphorus and decreased urinary phosphorus excretion. We determined that tenapanor reduces intestinal phosphate absorption predominantly through reduction of passive paracellular phosphate flux, an effect mediated exclusively via on-target NHE3 inhibition.
Topics: Adult; Aged; Animals; Base Sequence; Cell Membrane Permeability; Cells, Cultured; Electric Impedance; Epithelium; Female; Gastrointestinal Tract; Healthy Volunteers; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Ions; Isoquinolines; Male; Mice; Middle Aged; Phosphates; Potassium; Protons; Rats; Sodium; Sodium-Hydrogen Exchanger 3; Sulfonamides; Tight Junction Proteins; Young Adult
PubMed: 30158152
DOI: 10.1126/scitranslmed.aam6474 -
Pediatric Nephrology (Berlin, Germany) Jul 2017The kidney plays an essential role in maintaining homeostasis of ion concentrations in the blood. Because the concentration gradient of potassium across the cell... (Review)
Review
The kidney plays an essential role in maintaining homeostasis of ion concentrations in the blood. Because the concentration gradient of potassium across the cell membrane is a key determinant of the membrane potential of cells, even small deviations in serum potassium level from the normal setpoint can lead to severe muscle dysfunction, resulting in respiratory failure and cardiac arrest. Less severe hypo- and hyperkalemia are also associated with morbidity and mortality across various patient populations. In addition, deficiencies in potassium intake have been associated with hypertension and adverse cardiovascular and renal outcomes, likely due in part to the interrelated handling of sodium and potassium by the kidney. Here, data on the beneficial effects of potassium on blood pressure and cardiovascular and renal outcomes will be reviewed, along with the physiological basis for these effects. In some patient populations, however, potassium excess is deleterious. Risk factors for the development of hyperkalemia will be reviewed, as well as the risks and benefits of existing and emerging therapies for hyperkalemia.
Topics: Aldosterone; Cation Exchange Resins; Cell Membrane; Child; Heart Failure; Homeostasis; Humans; Hyperkalemia; Hypertension; Hypokalemia; Kidney; Membrane Potentials; Polymers; Potassium; Potassium, Dietary; Protein Serine-Threonine Kinases; Recommended Dietary Allowances; Renal Elimination; Renin-Angiotensin System; Respiratory Insufficiency; Risk Factors; Signal Transduction; Silicates; Sodium; Sodium Chloride Symporters; WNK Lysine-Deficient Protein Kinase 1
PubMed: 27194424
DOI: 10.1007/s00467-016-3411-8 -
Journal of Molecular Biology Aug 2021Potassium ion homeostasis is essential for bacterial survival, playing roles in osmoregulation, pH homeostasis, regulation of protein synthesis, enzyme activation,... (Review)
Review
Potassium ion homeostasis is essential for bacterial survival, playing roles in osmoregulation, pH homeostasis, regulation of protein synthesis, enzyme activation, membrane potential adjustment and electrical signaling. To accomplish such diverse physiological tasks, it is not surprising that a single bacterium typically encodes several potassium uptake and release systems. To understand the role each individual protein fulfills and how these proteins work in concert, it is important to identify the molecular details of their function. One needs to understand whether the systems transport ions actively or passively, and what mechanisms or ligands lead to the activation or inactivation of individual systems. Combining mechanistic information with knowledge about the physiology under different stress situations, such as osmostress, pH stress or nutrient limitation, one can identify the task of each system and deduce how they are coordinated with each other. By reviewing the general principles of bacterial membrane physiology and describing the molecular architecture and function of several bacterial K-transporting systems, we aim to provide a framework for microbiologists studying bacterial potassium homeostasis and the many K-translocating systems that are still poorly understood.
Topics: Bacteria; Bacterial Physiological Phenomena; Biological Transport; Homeostasis; Ion Transport; Membrane Potentials; Potassium; Potassium Channels; Structure-Activity Relationship
PubMed: 33798529
DOI: 10.1016/j.jmb.2021.166968