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Renal Physiology Renal Physiology Distal Convoluted Tubule | Arohan R. Subramanya*†‡ and David H. Ellison§ ¶ Abstract The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical Departments of *Medicine and †Cell practice. Biology, University of Clin J Am Soc Nephrol 9: 2147–2163, 2014. doi: 10.2215/CJN.05920613 Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ‡Veterans Affairs Introduction structure to glucocorticoids, such as cortisol, and both Pittsburgh Healthcare The distal convoluted tubule (DCT) is the portion aldosterone and cortisol bind to the mineralocorticoid System, Pittsburgh, of the nephron that is immediately downstream of receptor with nearly equal affinity (3). Although min- Pennsylvania; the macula densa. Although the DCT is the shortest eralocorticoid receptors are expressed throughout the Departments of §Medicine and | segment of the nephron, spanning only about 5 mm entire DCT, the DCT2 is sensitive to the actions of Physiology and in length in humans (1), it plays a critical role in a va- aldosterone, because it expresses an enzyme called Pharmacology, riety of homeostatic processes, including sodium chlo- 11-b hydroxysteroid dehydrogenase 2 (11-bHSD2). Oregon Health and ride reabsorption, potassium secretion, and calcium 11-bHSD2 metabolizes cortisol to the inactive metab- Science University, Portland, Oregon; and and magnesium handling. The DCT has a unique ca- olite cortisone, thereby preventing circulating gluco- ¶ Portland Veterans pacity to adapt to changes in hormonal stimuli and corticoids from binding to mineralocorticoid Affairs Medical the contents of the tubular lumen, and this process receptors expressed in the DCT2 (4). Because the min- Center, Portland, contributes to the pathophysiology of a number of eralocorticoid receptors in the DCT2 can only be oc- Oregon clinically relevant scenarios, including loop diuretic cupied by aldosterone, theDCT2ismoresensitive resistance and hyperaldosteronism. In recent years, than the DCT1 to changes in circulating aldosterone Correspondence: insights gained from Mendelian disorders of BP and levels. 11-bHSD2 is also expressed in other down- Dr. Arohan R. fi Subramanya, electrolyte imbalance, genetically modi ed animal stream nephron segments, including the CNT and Department of models, and molecular cloning and study of key the cortical collecting duct (CCD). For this reason, Medicine, Renal- components of the machinery that controls the di- the DCT2, CNT, and CCD are collectively termed the Electrolyte Division, verse ion transport processes housed in this segment aldosterone-sensitive distal nephron (5). University of have greatly expanded our understanding of distal Pittsburgh School of Cells of the DCT have a unique morphology that Medicine, S828A tubule function. In this article, we provide a focused matches their highly active physiology (Figure 1, in- Scaife Hall, 3550 overview and update of the molecular physiology of sets) (6). Their nuclei tend to be positioned to the Terrace Street, the DCT. apical side of the cell because of an extensive baso- Pittsburgh, PA 15261. lateral membrane that has numerous deep infoldings. Email: ars129@pitt. edu In addition, the cytosol on the basal aspect of DCT Distal Nephron Nomenclature and Anatomic cells is packed with mitochondria—in fact, cells of the Considerations DCT are among the most mitochondria-rich in the The term distal tubule has been used by anatomists kidney (7). These findings indicate that the DCT en- to denote the region of the nephron that extends down- gages in processes that require considerable ATP con- stream from the macula densa to the confluence of sumption and active transport of electrolytes driven another tubule (i.e., the collecting system) (Figure 1) (2). by the basolateral Na1-K1-ATPase. It includes two nephron segments, the DCT and the connecting tubule (CNT). The DCT can be further di- vided into two functionally distinct subsegments, re- Mechanism of Na1 Reabsorption in the DCT ferred to as the DCT1 and the DCT2 (also called the Apical Sodium Transport in the Early and Late DCTs early and late DCTs). The DCT reabsorbs roughly 5%–10% of the filtered The DCT1 and DCT2 can be distinguished by their sodium load (8). The thiazide-sensitive NaCl cotrans- differential responsiveness to the mineralocorticoid porter(NCC;TSC;SLC12A3)ischiefly responsible for aldosterone. Aldosterone is a steroid hormone that is this process. NCC is one of the major targets of thiazide- released from the adrenal gland in response to volume type diuretics; the other target is sodium-dependent depletion or hyperkalemia. It has a similar chemical chloride bicarbonate exchanger (NDCBE; SLC4A8), a www.cjasn.org Vol 9 December, 2014 Copyright © 2014 by the American Society of Nephrology 2147 2148 Clinical Journal of the American Society of Nephrology Figure 1. | A human nephron, showing the anatomic location of the distal tubule. The distal convoluted tubule (DCT) is divided into early and late segments, termed DCT1 and DCT2, respectively. The connecting tubule (CNT) is located immediately downstream of the DCT2. Insets compare DCT and CNT cell morphology. The cells of the DCT contain an extensive basolateral membrane system and are mitochondria-rich, 1 1 indicating high transport activity of the Na -K -ATPase. CNT cells, in contrast, contain fewer mitochondria and basolateral membrane in- vaginations, suggesting that they are less metabolically active. recently discovered Na1-driven chloride bicarbonate ex- (Figure 2) (15,16). ENaC-mediated sodium transport is elec- changer expressed in the CCD (9). This class of drugs is trogenic; thus, in the DCT2, movement of Na1 ions through commonly used to treat hypertension, edema, and nephro- ENaC without an accompanying anion leaves negative lithiasis and include the thiazides chlorothiazide, hydrochlo- charges in the lumen. Therefore, the transepithelial voltage rothiazide, and bendroflumethiazide (only available or sum of membrane potentials on the luminal and combined with nadolol in the United States) as well as the basolateral membranes of the DCT epithelium is lumen- thiazide-like diuretics metolazone, indapamide, and chlor- negative. As will be discussed below, this electrical gradient thalidone. As shown in Figure 2, in the DCT1, sodium ab- provides a driving force for the movement of other ions. sorption from the tubular lumen is chloride-dependent and Because ENaC is also expressed in the CNT and collecting entirely mediated by NCC (10). Because a negatively duct, the transepithelial voltage becomes progressively more charged chloride anion enters in 1:1 stoichiometry with a lumen-negative downstream of the DCT (17,18). sodium cation, this process is electrically silent or electro- neutral. Loss-of-function mutations of NCC cause Gitelman Basolateral Sodium Transport syndrome, an autosomal recessive salt wasting disorder In both subsegments of the DCT, after the transapical 1 1 that commonly presents with low-to-normal BP, elevated movement of Na through NCC and/or ENaC, Na is ex- renin levels, hypokalemia, metabolic alkalosis, hypocalciu- truded from the cytosol and into the peritubular fluid by the 1 1 ria, and hypomagnesemia (11). Thus, the phenotype of Na -K -ATPase (Figure 2). Because this electrogenic pump Gitelman syndrome is similar to the effects of thiazide exchanges sodium for potassium at a stoichiometry of 3:2, its diuretics. Most Gitelman mutations introduce changes into activity removes one positive charge from the intracellular the NCC polypeptide that cause the cotransporter to misfold space, resulting in the generation of a constant negative volt- (12). This results in enhanced recognition by a molecular age of 260 to 290 mV across the basolateral membrane chaperone protein called Hsp70, which binds to misfolded (19,20). Along the basolateral membrane, the intracellular NCC as it is being made in the endoplasmic reticulum and voltage becomes more negative with respect to extracellular targets it for degradation (13,14). voltage if the intracellular sodium concentration increases. NCC is expressed throughout the DCT, but the DCT2 This finding suggests that, in the DCT, a rise in luminal also exhibits an amiloride-sensitive sodium transport path- NCC- or ENaC-mediated sodium transport stimulates baso- way mediated by the epithelial sodium channel (ENaC) lateral Na1 extrusion through the Na1-K1-ATPase (19). This Clin J Am Soc Nephrol 9: 2147–2163, December, 2014 Distal Convoluted Tubule, Subramanya et al. 2149 ataxia, sensorineural deafness, and tubulopathy) by some investigators and SeSAME syndrome (seizures, sensorineu- ral deafness, ataxia, mantal retardation, and electrolyte im- balance) by others. The Gitelman-like phenotype seen in individuals with the syndrome is likely caused by impaired Kir4.1 function and potassium recycling at the basolateral membrane of the DCT (26). In the absence of Kir4.1 activity, 1 1 the activity of the Na -K -ATPase is reduced, resulting in 1 diminished transcellular Na reabsorption in the DCT (Figure 3). Recent studies indicate that patients with EAST/SeSAME
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