Thick ascending tubular cells in the loop of Henle: Regulation of electrolyte homeostasis

Thick ascending tubular cells in the loop of Henle: Regulation of electrolyte homeostasis

The International Journal of Biochemistry & Cell Biology 37 (2005) 1554–1559 Cells in focus Thick ascending tubular cells in the loop of Henle: Regu...

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The International Journal of Biochemistry & Cell Biology 37 (2005) 1554–1559

Cells in focus

Thick ascending tubular cells in the loop of Henle: Regulation of electrolyte homeostasis Fredrik Palm ∗ , Per-Ola Carlsson Department of Medical Cell Biology, Biomedical Center, Husargatan 3, P.O. Box 571, SE 751 23 Uppsala, Sweden Received 29 October 2004; received in revised form 31 January 2005; accepted 13 February 2005

Abstract Renal medullary tubular cells in the loop of Henle have crucial importance for the regulation of homeostasis of the extracellular fluid. These cells receive limited amount of blood and oxygen, and are also constantly challenged by the hypertonic environment. The medullary tubular cells in the last part of the loop of Henle have one of the highest known contents of mitochondria of all mammalian cells, reflecting their need for oxidative metabolism in order to sustain high ATP production for active transepithelial electrolyte transport. The commonly used diureticum furosemide targets one of the transporters present in these tubular cells with resulting diuresis. Several pathological states are associated with altered function of the medullary tubular cells, and the nephrotoxic substances tacrolimus and cyclosporine act on these cells. The specific Tamm–Horsfall glycoprotein is produced by medullary tubular cells. Alteration in the urinary excretion of this protein is used as marker of tubular damage. © 2005 Elsevier Ltd. All rights reserved. Keywords: Tubular cell; Electrolyte transport; Tamm–Horsfall protein; ROMK; CaSR; Kidney

Cell facts • Renal medullary tubular cells have one of the highest mitochondria densities of all mammalian cells. • Transport about 300 g of NaCl per 24 h during normal conditions. • Produce the specific Tamm–Horsfall glycoprotein.

1. Introduction The anatomical border between the renal cortex and the renal medulla is distinctively outlined by vascular ∗ Corresponding author. Tel.: +46 18 471 4182; fax: +46 18 471 4938. E-mail address: [email protected] (F. Palm).

1357-2725/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2005.02.007

structures consisting of the arcuate vessels. The deeper situated renal medulla consists of two morphologically different parts, i.e. outer and inner zones. The outer zone is further divided into an outer and an inner stripe. The functional units of the kidney, the nephrons, consist of a tubular structure beginning with the glomerulus enclosed in the Bowman’s capsule, continuing with the proximal tubule, loop of Henle, distal

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tubule, connecting tubule and finally the collecting duct ending in the renal pelvis. Although every nephron has all the different parts described above, only the nephrons from the deeper situated juxtamedullary glomeruli reach with their loops of Henle into the inner zone of the renal medulla. Three functionally different segments of the loop of Henle can be outlined in these nephrons, namely the descending thin segment situated in the inner stripe of the outer zone and in the inner zone of the medulla, the ascending thin segment located in the inner zone of the medulla, and finally the ascending thick segment located partly in outer part of the inner zone, but mainly in the outer zone of the medulla (Fig. 1). The descending thin segment has epithelium type II, which is characterized by thick well-differentiated cells with few microvilli and many mitochondria. A progressive transition to epithelium type III occurs further down into the medulla. The deeper situated segment consists of flat cells and is highly permeable to water and most electrolytes. The concentration of urine that occurs in the thin descending segment is due to passive transepithelial diffusion of water. The medullary tubular cells constituting the thin ascending segment is of type IV epithelium, typically with cells joined by complicated interdigitations and numerous tight junctions, which creates an efficient barrier to water but is permeable to urea, chloride and sodium.

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The thin ascending segment has also been shown to possess properties of active transport (Reeves, Winters, & Andreoli, 2001). The medullary thick ascending segment also consist of epithelium type IV, and has cells with short and few microvilli containing the specific Tamm–Horsfall glycoprotein (Serafini-Cessi, Malagolini, & Cavallone, 2003), and also very high abundance of mitochondria. The medullary thick ascending segment is highly impermeable to water, and is the major site of transepithelial electrolyte transport in the loop of Henle. Type I epithelial cells are only found in short limbs originating from superficial glomeruli (Dieterich, Barrett, Kriz, & Bulhoff, 1975).

2. Cell origin and plasticity The first detectable rudiment of a kidney during the embryonic development consists of mesenchymal stem cells attached to the epithelial bud from the Wolffian duct (Sax´en, 1987). Already early during development, the entire cell cluster is surrounded by a complex vasculature. The cell–cell interaction of the mesenchymal and the epithelial cells initiates the epithelial cells to form the ureter and the collecting ducts, while the mesenchymal cells differentiate to form new epithelium (Ekblom, 1992). The newly formed epithelium will

Fig. 1. Cross section of the inner stripe of the outer medulla of a mouse kidney displaying medullary tubular cells from different parts of the loop of Henle; hematoxylin–eosin.

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later constitute the epithelium of both the glomeruli and the renal tubules, thus being the origin of renal medullary tubular cells. The mesenchymal cells, which do not differentiate to epithelial cells, will form the stromal cell compartment. No more nephrons are formed postnatally in humans. Instead, maturation occurs, including the formation of transporting proteins in the epithelial cells, which is of great importance for the final development of fully functional nephrons (Ekblom, 1992).

3. Functions Generally, medullary tubular cells are of great importance for the maintenance of homeostasis in the

extracellular space and the formation of concentrated urine. The latter is achieved by the transepithelial transport of electrolytes and urea, resulting in the extracellular hypertonicity in the renal medulla. The medullary tubular cells in the thin descending and ascending segments of the loop of Henle are epithelial cells with few mitochondria and no brush borders. This is also reflected in the low amount of Na+ /K+ -ATPase present in the thin segments, in vast contrast to the very high density of Na+ /K+ -ATPase found in the ascending thick segment (Katz, Doucet, & Morel, 1979). About 25% of the filtrated sodium is reabsorbed in the loop of Henle, i.e. by the renal medullary tubular cells constituting the thick ascending segment (Greger, 2000), making the sodium transport in this part of the nephron to exceed even that in the proximal tubulus. It has been reported

Fig. 2. Segment of the thick ascending loop of Henle with the renal medullary tubular cells and outlining the most important transport proteins. Na+ is transported from the tubular lumen either by active transport through the intracellular pathway, involving both specific transporters in the apical (Na+ /K+ /2Cl− -cotransporter and Na+ /H+ -exchanger) and in the basolateral membrane (Na+ /K+ -ATPase) or the paracellular route driven by the potential difference created by the transport of Cl− . The K+ transported into the cell by the Na+ /K+ /2Cl− -cotransporter is recirculated to the tubular lumen through K+ -channels (ROMK), or transported across the basolateral membrane by KCl and KHCO3 − -cotransporters (not shown). These medullary cells also have important properties for the maintenance of acid–base homeostasis, demonstrated by the regulated excretion of NH4 + and reabsorbtion of HCO3 − . The potential values are given with the peritubular fluid as the reference.

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that up to 44% of the intracellular volume is occupied by mitochondria in the epithelial cells of the thick ascending segment (Chamberlin, LeFurgey, & Mandel, 1984), reflecting the high-energy demand and oxygen consumption of the medullary tubular cells (Palm, Cederberg, Hansell, Liss, & Carlsson, 2003; Palm et al., 2004). Furthermore, for every Na+ transported by the Na+ /K+ -ATPase in the thick ascending segment, another Na+ ion is transported paracellularly (Fig. 2). The Na+ transport consumes significant amount of the ATP produced in these cells, but the resulting Na+ gradient is used by many of the secondary active transporters located both in the apical and the basolateral membranes. The most prominent Na+ -transporter in the apical membrane is the Na+ /K+ /2Cl− -cotransporter, which has been found to be strictly regulated by the Ca2+ sensing receptor (CaSR) located in the basolateral membrane (Fig. 2) (Hebert, 2004). Increased extracellular Ca2+ activates the CaSR, which results in the inhibition of the Na+/K+/2Cl− -cotransport, thus reducing the negative potential in the interstitium and thereby inhibition of the paracellular transport of Ca2+ . The affinity of Ca2+ for the CaSR is affected by alterations in the ionic strength, resulting in a functional salinity sensor, which is believed to be of great importance for the maintenance of the electrolyte balance (Hebert, 2004). A pivotal role for the Na+ /K+ /2Cl− -cotransporter is the recycling of K+ through the K+ -channels (ROMK) in the apical membrane (Fig. 2) (Wang, 2004). During alterations in K+ food intake, the transport of K+ from the tubular lumen into the interstitium changes accordingly, revealing the important regulatory function of the thick ascending loop of Henle in the maintenance of the K+ balance in the extra cellular fluid (Wang, 2004). The activity of the different transporters in the medullary tubular cells of the thick ascending loop of Henle is under strict regulation by several hormones. Vasopressin stimulates the Na+ /K+ /2Cl− -cotransport in numerous mammals through activation of adenylate cyclase, with subsequent increase in intracellular adenosine 3 ,5 -cyclic monophosphate (cAMP), while angiotensin II have been shown to reduce cAMP via the phospholipase C pathway (De Rouffignac, 1995). The Na+ /K+ /2Cl− -transporters is also stimulated by parathyroid hormone, calcitonin and the ␤-adrenergic agonist isoproterenol; the biochemical and physiolog-

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ical response to all of these agonists are attenuated by prostaglandin E2 (De Rouffignac, 1995). The resulting increase in chloride transport after cAMP stimulation increases the reabsorption of Ca2+ , K+ and Mg2+ through the paracellular pathway, due to the establishment of a greater positive potential in the lumen. It has also been shown that insulin can affect the transport of Mg2+ independently of the Na+ transport and transepithelial potential (De Rouffignac, 1995), and that dopamine inhibits Na+ /K+ -ATPase in the thick ascending segment (Aperia, 2000). Transepithelial transport of several other ions and molecules also occurs along the loop of Henle. The most important transport mechanisms are illustrated in Fig. 2. Both insulin-dependent (GLUT4) and insulinindependent glucose transporters (GLUT1) have been found in the medullary tubular cells, with highest abundance in the cells constituting the thick ascending segment (Joost & Thorens, 2001). The blood perfusion and availability of oxygen in the renal medulla is greatly reduced towards the papillary tip (Palm et al., 2003, 2004), a finding that is further supported by the metabolic enzymes present in cells from different parts of the renal medulla (Gullans & Mandel, 1992). Generally, high amounts of glycolytic enzymes are present throughout the medullary structure, which is reflected in normally high extracellular lactate concentrations (Palm et al., 2003). Tricarboxylic acid enzymes are only present in the most superficial parts of the thick ascending segment. Furthermore, very low amounts of fatty acid oxidizing and gluconeogenic enzymes are found in all medullary tubular cells during normal conditions. However, if deprived of glucose and lactate these cells can use the intracellular storage of glycogen or utilize fatty acids and ketone bodies (Gullans & Mandel, 1992). The oxygen consumption is closely related to the transport of electrolytes, thus inhibition of the Na+ /K+ -ATPase rapidly decreases the oxygen demand by up to 50% (Gullans & Mandel, 1992).

4. Associated pathologies The commonly used loop diuretic furosemide blocks the Na+ /K+ /2Cl− -cotransport, resulting in increased urinary flow due to reduced reabsorption of

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electrolytes. Notably, the tubuloglomerular feed-back (TGF) system utilizes the same transporter to sense the amount of, primarily, chloride reaching the macula densa cells. Addition of furosemide therefore also results in a vanished TGF response, which otherwise would have counteracted the effect of the diureticum. Inhibition of the medullary Na+ /K+ /2Cl− cotransport also decreases the transepithelial potential (Fig. 2), resulting in reduced paracellular Ca2+ reabsorption and subsequent calciuresis. Mutations in the CaSR gene, resulting in either increased activity or loss of function, alter the urinary excretion of calcium and thereby the extracellular concentration. Mutations in the CaSR gene have recently been reported to be associated with Bartter syndrome (Hebert, 2004). Bartter syndrome can also result from mutations in the ROMK (Wang, 2004). The thick ascending segment of the loop of Henle is particularly susceptible to renal hypoxia. Hypoxia can result in loss of urinary concentration capacity or sustained renal failure (Eckardt, Rosenberger, Jurgensen, & Wiesener, 2003). Several factors can aggravate medullary hypoxia, including diabetes (Palm et al., 2003, 2004), intravenous injection of iodinated contrast agents (Persson, Hansell, & Liss, in press), and several toxic substances such as tacrolimus and cyclosporine (Morales, Andres, Rengel, & Rodicio, 2001). Already moderate renal medullary hypoxia results in morphological alterations of the loop of Henle. Hypoxia-induced endogenous release of cytokines and angiotensin II has been shown to induce fibrosis in the renal medulla. Altered urinary excretion of Tamm–Horsfall protein is regarded as a trustworthy sign of tubular damage and is commonly used clinically (Serafini-Cessi et al., 2003). Furthermore, Tamm–Horsfall protein per se, produced either by the cells in the thick ascending segment of the loop of Henle, or by the cells constituting the initial part of the distal tubuli, is believed to be involved in several disorders, including cast nephropathy, urolithiasis, tubulointerstitial nephritis and several mutagenic diseases (Serafini-Cessi et al., 2003).

Acknowledgements Due to the limitation of the references allowed for this review, a sincere apology is given for all the

omitted references that have contributed to the understanding of the function of the renal medullary tubular cells.

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