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Renal Physiology RenalCJASN Physiology ePress. Published on May 1, 2014 as doi: 10.2215/CJN.08580813 Regulation of Potassium Homeostasis Biff F. Palmer Abstract Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium Department of Internal Medicine, commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium University of Texas metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a Southwestern Medical resource for teaching trainees and medical students. Center, Dallas, Texas Clin J Am Soc Nephrol ▪: ccc–ccc, 2015. doi: 10.2215/CJN.08580813 Correspondence: Dr. Biff F. Palmer, Department of 1 Introduction Catecholamines regulate internal K distribution, with Internal Medicine, Potassium plays a key role in maintaining cell function. a-adrenergic receptors impairing and b-adrenergic recep- University of Texas 1 1 1 b – Southwestern Medical Almost all cells possess an Na -K -ATPase, which tors promoting cellular entry of K . 2-Receptor induced pumps Na1 out of the cell and K1 into the cell and 1 Center, 5323 Harry stimulation of K uptake is mediated by activation of the Hines Boulevard, 1 1 . 1 1 leads to a K gradient across the cell membrane (K in Na -K -ATPase pump. These effects play a role in reg- Dallas, TX 75390. 1 1 K out) that is partially responsible for maintaining the ulating the cellular release of K during exercise (6). Email: biff.palmer@ potential difference across the membrane. This poten- Under normal circumstances, exercise is associated utsouthwestern.edu tial difference is critical to the function of cells, partic- with movement of intracellular K1 into the interstitial ularly in excitable tissues, such as nerve and muscle. space in skeletal muscle. Increases in interstitial K1 The body has developed numerous mechanisms for de- canbeashighas10–12 mM with severe exercise. 1 fense of serum K . These mechanisms serve to Accumulation of K1 is a factor limiting the excitabil- 1 maintain a proper distribution of K within the body ity and contractile force of muscle accounting for the 1 as well as regulate the total body K content. development of fatigue (7,8). Additionally, increases in interstitial K1 play a role in eliciting rapid vaso- fl Internal Balance of K1 dilation, allowing for blood ow to increase in exer- The kidney is primarily responsible for maintaining cising muscle (9). During exercise, release of b total body K1 contentbymatchingK1 intake with K1 catecholamines through 2 stimulation limits the 1 rise in extracellular K1 concentration that otherwise excretion. Adjustments in renal K excretion occur 1 over several hours; therefore, changes in extracellular occurs as a result of normal K release by contracting K1 concentration are initially buffered by movement muscle. Although the mechanism is likely to be mul- 1 tifactorial, total body K1 depletion may blunt the ac- of K into or out of skeletal muscle. The regulation of 1 K1 distribution between the intracellular and extracel- cumulation of K into the interstitial space, limiting fl lular space is referred to as internal K1 balance. The blood ow to skeletal muscle and accounting for the most important factors regulating this movement under association of hypokalemia with rhabdomyolysis. – normal conditions are insulin and catecholamines (1). Changes in plasma tonicity and acid base disorders fl 1 After a meal, the postprandial release of insulin also in uence internal K balance. Hyperglycemia functions to not only regulate the serum glucose leads to water movement from the intracellular to concentration but also shift dietary K1 into cells until extracellular compartment. This water movement fa- 1 1 1 fl the kidney excretes the K load re-establishing K ho- vors K ef ux from the cell through the process of meostasis. These effects are mediated through insulin solvent drag. In addition, cell shrinkage causes intra- 1 binding to cell surface receptors, which stimulates glu- cellular K concentration to increase, creating a more 1 cose uptake in insulin-responsive tissues through the favorable concentration gradient for K efflux. Min- insertion of the glucose transporter protein GLUT4 eral acidosis, but not organic acidosis, can be a cause 1 1 1 (2,3). An increase in the activity of the Na -K -AT- of cell shift in K . As recently reviewed, the general 1 1 Pase mediates K uptake (Figure 1). In patients with effect of acidemia to cause K loss from cells is not the metabolic syndrome or CKD, insulin-mediated glu- because of a direct K1-H1 exchange, but, rather, is cose uptake is impaired, but cellular K1 uptake re- because of an apparent coupling resulting from ef- mains normal (4,5), demonstrating differential fects of acidosis on transporters that normally regu- regulation of insulin-mediated glucose and K1 uptake. late cell pH in skeletal muscle (10) (Figure 2). www.cjasn.org Vol 0 ▪▪▪,2015 Copyright © 2014 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology b Figure 1. | The cell model illustrates 2-adrenergic and insulin- 1 b mediated regulatory pathways for K uptake. 2-Adrenergic and insulinbothleadtoK1 uptake by stimulating the activity of the Na1-K1-ATPase pump primarily in skeletal muscle, but they do so b through different signaling pathways. 2-Adrenergic stimulation leads to increased pump activity through a cAMP- and protein kinase A (PKA)–dependent pathway. Insulin binding to its receptor leads to phosphorylation of the insulin receptor substrate pro- tein (IRS-1), which, in turn, binds to phosphatidylinositide 3-kinase (PI3-K). The IRS-1–PI3-K interaction leads to activation of 3-phosphoinositide–dependent protein kinase-1 (PDK1). The stimulatory effect of insulin on glucose uptake and K1 uptake diverge at this point. An Akt-dependent pathway is responsible for membrane insertion of the glucose transporter GLUT4, whereas activation of atypical protein kinase C (aPKC) leads to membrane insertion of the Na1-K1-ATPase pump (reviewed in ref. 3). 1 1 Intracellular K serves as a reservoir to limit the fall in Figure 2. | The effect of metabolic acidosis on internal K balance in 1 extracellular K concentrations occurring under patho- skeletal muscle. (A) In metabolic acidosis caused by inorganic anions 1 logic conditions where there is loss of K from the body. (mineral acidosis), the decrease in extracellular pH will decrease the 1 1 1 The efficiency of this effect was shown by military recruits rate of Na -H exchange (NHE1) and inhibit the inward rate of Na -3HCO3 cotransport (NBCe1 and NBCe2). The resultant fall in in- undergoing training in the summer (11). These subjects 1 1 1 1 tracellular Na will reduce Na -K -ATPase activity, causing a net were able to maintain a near-normal serum K concentra- 1 1 . loss of cellular K . In addition, the fall in extracellular HCO3 concen- tion despite daily sweat K loses of 40 mmol and an 11- 2 2 1 tration will increase inward movement of Cl by Cl-HCO exchange, day cumulative total body K deficit of approximately 400 1 1 2 1 further enhancing K effluxbyK -Cl cotransport. (B) Loss of K from mmol. 1 the cell is much smaller in magnitude in metabolic acidosis caused byan Studies in rats using a K clamp technique afforded in- organic acidosis. In this setting, there is a strong inward flux of the or- 1 sight into the role of skeletal muscle in regulating extracel- ganic anion and H through the monocarboxylate transporter (MCT; 1 lular K concentration (12). With this technique, insulin is MCT1 and MCT4). Accumulation of the acid results in a larger fall in 1 1 administered at a constant rate, and K is simultaneously intracellular pH, thereby stimulating inward Na movement by way of 1 1 1 infused at a rate designed to prevent any drop in plasma Na -H exchange and Na -3HCO3 cotransport. Accumulation of in- 1 1 1 1 1 tracellular Na maintains Na -K -ATPase activity, thereby mini- K concentration. The amount of K administered is pre- 1 sumed to be equal to the amount of K1 entering the in- mizing any change in extracellular K concentration. tracellular space of skeletal muscle. In rats deprived of K1 for 10 days, the plasma K1 con- centration decreased from 4.2 to 2.9 mmol/L. Insulin- expression and activity facilitate the ability of skeletal muscle mediated K1 disappearance declined by more than 90% to buffer declines in extracellular K1 concentrations by do- compared with control values. This decrease in K1 uptake nating some component of its intracellular stores. was accompanied by a .50% reduction in both the activity There are differences between skeletal and cardiac and expression of muscle Na1-K1-ATPase, suggesting that muscle in the response to chronic K1 depletion. Although decreased pump activity might account for the decrease in skeletal muscle readily relinquishes K1 to minimize the insulin effect. This decrease in muscle K1 uptake, under drop in plasma K1 concentration, cardiac tissue K1 con- conditions of K1 depletion, may limit excessive falls in ex- tent remains relatively well preserved. In contrast to tracellular K1 concentration that occur under conditions of the decline in activity and expression of skeletal muscle insulin stimulation. Concurrently, reductions in pump Na1 -K1 -ATPase, cardiac Na1 -K1 -ATPase pool size Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Normal Potassium Homeostasis, Palmer 3 increases in K1-deficient animals.
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