Loops of Henle

The kidney generally contains two populations of nephrons, long-looped and short-looped, which merge to form a common collecting duct system (see Figure 10.2 ). Both types of nephrons have loops of Henle that are arranged in a folded or hairpin configuration. Short-looped nephrons generally have glomeruli that are located more superficially in the cortex and have loops that bend in the outer medulla. Long-looped nephrons generally have glomeruli that are located more deeply within the cortex and have loops that bend at various levels of the inner medulla. Long-looped nephrons also contain a thin ascending limb, a segment that is not present in short-looped nephrons. Thin ascending limbs are found only in the inner medulla. The inner-outer medullary border is defined by the transition from thin to thick ascending limbs. Thus the outer medulla contains only thick ascending limbs, regardless of the type of loop. The long-looped nephrons bend at various levels of the inner medulla from the inner-outer medullary border to the papillary tip. Thus progressively fewer loops of Henle extend to deeper levels of the inner medulla. Some mammalian kidneys, such as human kidneys, also contain cortical nephrons, which are nephrons whose loops of Henle do not reach into the medulla.

The loops of Henle receive tubule fluid from the proximal convoluted tubules. Tubule fluid exits the thick ascending limbs of both long- and short-looped nephrons, and from cortical nephrons in species that have them, and flows into distal convoluted tubules (DCTs). Thus the descending and ascending limbs of the loops of Henle have a countercurrent flow configuration and are composed of several different nephron segments (see Figure 10.2 ). The descending portion of the loop of Henle consists of the S2 proximal straight tubule in the medullary ray, the S3 proximal straight tubule (or pars recta) in the outer stripe of the outer medulla, and the thin descending limb in the inner stripe of the outer medulla and the inner medulla. The descending thin limb of short-looped nephrons differs structurally and functionally from the descending thin limb of long-looped nephrons.

The location of the descending thin limb of short-looped nephrons within the outer medulla is illustrated in Figure 10.3 (labeled in green). The descending thin limbs of short-looped nephrons surround the vascular bundles in the outer medulla and tend to be organized in a ringlike pattern (see Figure 10.3 inset ). Thin descending limbs of long-looped nephrons in the outer medulla differ morphologically and functionally from thin descending limbs of long-looped nephrons in the inner medulla. The histologic transition from the outer medullary to the inner medullary type of thin descending limbs of long-looped nephrons is gradual and often occurs at some distance into the inner medulla, rather than strictly at the inner-outer medullary border as is the case for the transition between thin and thick ascending limbs.

Triple immunolabeling of rat renal medulla showing localization of UT-A2 (green), marking late thin descending limbs from short-looped nephrons, von Willebrand factor (blue) marking endothelial cells of vasa recta, and aquaporin-1 (red) marking thin descending limbs from outer medullary long-looped nephrons and early short-looped nephrons. Inset shows a cross section of a vascular bundle demonstrating that UT-A2–positive thin descending limbs from short-looped nephrons surround the vascular bundles in the deep part of the outer medulla. IM, Inner medulla; IS, inner stripe of outer medulla; OS, outer stripe of outer medulla; VBa, vascular bundles in outer part of inner stripe; VBb, vascular bundles in inner part of inner stripe.

(From Wade JB, Lee AJ, Liu J, et al: UT-A2: a 55 kDa urea transporter protein in thin descending limb of Henle’s loop whose abundance is regulated by vasopressin. Am J Physiol Renal Physiol 278:F52-F62, 2000.)

Pannabecker, Dantzler, and coworkers used immunohistochemical labeling and computer-assisted reconstruction to provide new detail about the functional architecture of the rat inner medulla. Figure 10.4 shows a computerized reconstruction of the inner medullary portion of several long-looped nephrons from rats that are labeled using antibodies to the water channel aquaporin-1 (AQP1, shown in red) and the kidney-specific chloride channel 1 (ClC-K1; shown in green). AQP1 is a marker of thin descending limbs of long-looped nephrons in the outer medulla, and AQP1 is detected in thin descending limbs of long-looped nephrons in the inner medulla for a variable distance. However, AQP1 was not found in thin descending limbs of loops of Henle that turn within the upper first millimeter of the inner medulla. Correspondingly, Zhai and colleagues determined that AQP1 was not detectable along the entire length of thin descending limbs of short-looped rat nephrons. In contrast, thin descending limbs of loops of Henle that turn below the first millimeter have three discernible functional subsegments: the upper 40% express AQP1, whereas the lower 60% do not. ClC-K1 is a marker of the thin ascending limb–type epithelium. It is first detected in the final approximately165 µm of the thin descending limb. Thus, ClC-K1 is detected before the bend of the loops of Henle, consistent with several morphologic studies that demonstrate that the descending limb to ascending limb transition occurs before the loop bend. A substantial portion of the inner medullary thin descending limb of long-looped nephrons did not express either AQP1 or ClC-K1, as indicated in gray.

Computer-assisted reconstruction of loops of Henle from rat inner medulla showing expression of aquaporin-1 (AQP1; red ) and kidney-specific chloride channel 1 (ClC-K1; green ); gray regions (B-crystallin) express undetectable levels of AQP1 and ClC-K1. Loops are oriented along the corticopapillary axis, with the left edge of each image nearer the base of the inner medulla. A, Thin limbs that have their bends within the first millimeter beyond the outer-inner medullary boundary. Descending segments lack detectable AQP1. ClC-K1 is expressed continuously along the prebend segment and the thin ascending limb. B, Loops that have their bends beyond the first millimeter of the inner medulla. AQP1 is expressed along the initial 40% of each thin descending limb and is absent from the remainder of each loop. ClC-K1 is expressed continuously along the prebend segment and the thin ascending limb. C, Enlargement of near-bend regions of four thin limbs from box in B . ClC-K1 expression, corresponding to thin descending limb prebend segment, begins, on average, 165 µm before the loop bend (arrows). Scale bars, 500 µm ( A and B ) and 100 µm ( C ).

(From Pannabecker TL, Dantzler WH, Layton HE, et al: Role of three-dimensional architecture in the urine concentrating mechanism of the rat renal inner medulla. Am J Physiol Renal Physiol 295:F1271-F1285, 2008.)

The deepest portions of descending thin limbs have low water permeability and reduced AQP1. It has been proposed, but not demonstrated experimentally, that urine concentration would be improved by the presence of a urea-Na ⁺ or urea-Cl ⁻ cotransporter in the AQP1-null portion of the thin descending limb. These deep AQP1-null segments, prebend segments, and thin ascending limbs lie equally near the collecting ducts. However, the distal 30% of thin ascending limbs of the longest loops of Henle lie distant from collecting ducts. Based upon these findings, Pannabecker and colleagues hypothesize that descending and ascending thin limbs enter and exit collecting duct clusters in a manner that is important for the generation and maintenance of the osmolality gradient within the inner medulla. These anatomic relationships result in isolated interstitial nodal spaces that may facilitate preferential mixing of solutes and fluid within the inner medulla.

Pannabecker and colleagues have also found evidence for mixed descending- and ascending-type thin limbs of the loops of Henle in the inner medulla. The ascending portions of the loops of Henle consist of the thin ascending limbs (which are present only in the long-looped nephrons of the inner medulla), the medullary thick ascending limbs in the inner and outer stripes of the outer medulla, and the cortical thick ascending limbs in the medullary rays.

Distal Tubule Segments in the Cortical Labyrinth

After tubule fluid exits the loop of Henle through the cortical thick ascending limb, it enters the DCT, which is located in the cortical labyrinth. In most mammalian species, several distal tubules merge to form a connecting tubule arcade. The connecting tubular cells express both the vasopressin-regulated water channel, aquaporin-2 (AQP2), and the type 2 vasopressin receptor (V2R), suggesting that the arcades are sites of vasopressin-regulated water reabsorption, similar to collecting ducts (see later). Tubule fluid exits the connecting tubules within the arcades and enters the initial collecting tubules, located in the superficial cortex, and then into the cortical collecting ducts. In most rodent species that have been studied, several nephrons merge to form a single cortical collecting duct.

Collecting Duct System

The collecting duct system spans all regions of the kidney, starting in the cortex and running to the tip of the inner medulla (see Figure 10.2 ). The collecting ducts are arranged parallel to the loops of Henle in the medullary rays, outer medulla, and inner medulla. Like the loops of Henle, several morphologically and functionally discrete segments are contained within the collecting duct system. In general, the collecting ducts descend straight through the medullary rays and outer medulla without joining with other collecting ducts. However, several collecting ducts merge as they descend within the inner medulla, resulting in a progressive reduction in the number of inner medullary collecting ducts (IMCDs) from the inner-outer medullary border to the papillary tip. The tapered structure of the renal papilla results from the reduction in collecting duct number, accompanied by a progressive reduction in the number of loops of Henle, reaching the deepest levels of the inner medulla.

Detailed studies of inner medullary structure, both by Kriz and coworkers and in later studies by Pannabecker and Dantzler, found that the IMCDs in the inner medullary base (initial IMCDs) form clusters that coalesce along the corticomedullary axis. The thin descending limbs are predominantly present at the periphery of these clusters and appear to form an asymmetric ring around each collecting duct cluster, whereas the thin ascending limbs are distributed relatively uniformly among the collecting ducts and thin descending limbs.

Pannabecker and Dantzler identified three population groups of loops of Henle in Munich-Wistar rats, distinguished by the position of the thin ascending limb at the base of the inner medulla and by differing loop length ( Figure 10.5 ). Group 1 loops have thin ascending limbs that are interposed between collecting ducts and reach a mean length of 700 µm into the inner medulla. Group 2 loops have thin ascending limbs that are adjacent to just one collecting duct and reach a mean length of 1500 µm. Group 3 loops have thin ascending limbs that lie more than 0.5 tubule diameters from a collecting duct and reach a mean length of 2200 µm. As the collecting ducts coalesce and the shorter loops of Henle disappear, the originating portions of the longer thin ascending limbs run alongside the collecting ducts for a substantial distance.

Spatial relationships between thin descending limbs (red tubules), thin ascending limbs (green tubules), and collecting ducts (dark blue tubules).

Thin ascending limbs were categorized into three groups related to their lateral proximity to collecting ducts. Members of each group are shown in a transverse section located at the base of the inner medulla. A, Group 1. B, Group 2. C, Group 3. A-C, Open red figures represent aquaporin-1 (AQP1)–null thin descending limbs, solid red figures represent AQP1-expressing thin descending limbs, white outlined figures represent thin ascending limbs not associated with the collecting duct cluster, and light blue figures represent collecting ducts not associated with the collecting duct cluster. Two prebend segments from group 1 are included in A . One thin ascending limb from each of groups 2 and 3 ( B and C ) extends below the region of reconstruction, and their thin descending limbs were therefore not reconstructed. A′ , B′ , and C′ show thin descending limbs and collecting ducts. Gray tubules represent AQP1-null thin descending limbs. A″, B″, and C″ show thin ascending limbs and collecting ducts. Scale bars, 100 µm.

(From Pannabecker TL, Dantzler WH: Three-dimensional lateral and vertical relationships of inner medullary loops of Henle and collecting ducts. Am J Physiol Renal Physiol 287:F767-F774, 2004.)

Generation of the Axial Sodium Chloride Gradient in the Renal Outer Medulla

A sustained osmolality gradient is maintained along the corticomedullary axis of the outer medulla (see Figure 10.8 ); that gradient, which is present in both diuresis and antidiuresis, arises mostly from an accumulation of NaCl. The gradient is generated by the concentrating mechanism of the outer medulla. General considerations circumscribe the nature of that mechanism. Because the axial osmolality gradient is present in both diuresis and antidiuresis (in which the outer medullary collecting duct is water permeable to varying degrees), the accumulation of NaCl in the outer medulla cannot depend on a sustained osmolality difference across the collecting duct epithelium. Thus the concentrating mechanism must depend on the loops of Henle, on the vasculature, and on their interactions within the outer medulla. Moreover, mass balance of water and NaCl must be maintained; thus, for example, concentrated fluid that flows into the inner medulla must be balanced by dilute fluid that, in the presence of vasopressin, is absorbed from the cortical collecting duct, dilutes the cortical interstitial fluid, enters the cortical vasculature, and thus participates in maintaining an appropriate systemic level of blood plasma osmolality.

It has long been believed that the osmolality gradient of the outer medulla is generated by means of countercurrent multiplication of a single effect (“Vervielfältigung des Einzeleffektes”). In this paradigm, proposed by Kuhn and Ryffel in 1942, osmotic pressure is raised along parallel but opposing flows in nearby tubes that are made contiguous by a hairpin turn ( Figure 10.9 ): a transfer of solute from one tubule to another (i.e., a single effect) would augment (multiply), or reinforce, the osmotic pressure in the parallel flows. Thus, by means of the countercurrent configuration, a small transverse osmotic difference would be multiplied into a relatively large difference along the axes of flow. In support of this paradigm, Kuhn and Ryffel provided both a mathematical model and an apparatus that exemplified countercurrent multiplication.

A, Countercurrent multiplication by means of NaCl transfer from an ascending flow to a descending flow. B, Countercurrent multiplication by means of water withdrawal from a descending flow. NaCl transport from the ascending flow into the interstitium raises interstitial osmolality; this results in passive water transport from the descending flow, which has lower osmolality than the interstitium. In both panels, tubule fluid flow direction is indicated by blue arrows ; increasing osmolality is indicated by darkening shades of blue . Ascending flow may be considered to be in the thick ascending limb of Henle (TAL) and descending flow in the descending limb of Henle (DL). Thick blue lines indicate that a tubule is impermeable to water; thin lines indicate high permeability to water.

As anatomic and physiologic understanding of the renal medulla increased, the countercurrent multiplication paradigm was reinterpreted and modified. In 1951 Hargitay and Kuhn put the paradigm in the context of specific renal tubules. The loop of Henle was identified with the parallel tubes joined by a hairpin turn as proposed by Kuhn and Ryffel. Thus the loops of Henle were proposed as the source of the outer medullary gradient, and that gradient was hypothesized to draw water out of water-permeable collecting ducts. In 1959 Kuhn and Ramel used a mathematical model to show that active transport of NaCl from thick ascending limbs could serve as the single effect. Subsequent physiologic experiments confirmed the active NaCl transport and the osmotic absorption of water from collecting ducts. Experiments indicating high water permeability in hamster descending limbs of short loops and in descending limbs of long loops suggested that the accumulation of NaCl from thick limbs concentrated descending limb tubule fluid by osmotic water withdrawal, rather than by NaCl addition (see Figure 10.9 ).

Doubts have arisen about whether the paradigm of countercurrent multiplication provides an accurate representation of the means by which the gradient is generated in the mammalian outer medulla. Several weaknesses have been noted:

• 1.
  

  The descending limbs of short loops are anatomically separated from ascending limbs, with inner stripe portions of short loops near (or within) the vascular bundles and thick limbs near the collecting ducts. This configuration is not consistent with direct interactions between counterflowing limbs.

  
  
• 2.
  

  In short-looped rat nephrons, Wade and associates found that AQP1 is not expressed in portions of descending limb segments in the distal inner stripe. Zhai and colleagues found that AQP1 is not expressed in descending limbs of short loops in the inner stripes of mice, rats, and humans. The absence of AQP1 suggests that the assumption of high water permeability in descending limbs of short loops merits further experimental study. (Dantzler and coworkers have found that the AQP1-null segments of descending limbs in the inner medulla are essentially impermeable to water. )

  
  
• 3.
  

  Using transport rates based on measured sodium-potassium adenosine triphosphatase (Na ⁺ -K ⁺ -ATPase) activities, mathematical models predict substantial trans­epithelial NaCl gradients along the medullary portions of thick limbs ; this seems contrary to the notion of a small single effect.

  
  
• 4.
  

  It may well be that the concentrating mechanism of the outer medulla is placed under increased load, not less, if it has to concentrate water flowing in, and absorbed from, the descending limbs of short loops.

  
  
• 5.
  

  The absorption of water from the outer medullary portions of long loops has sometimes been considered to participate in a generalized form of countercurrent multiplication, and this may be the case for long loops that extend for sufficiently short distances into the inner medulla. However, in sufficiently long loops, tubule fluid is likely to be much altered by urea secretion and passive NaCl absorption within the inner medulla.

From these considerations, it seems reasonable therefore to hypothesize that the outer medullary osmolality gradient arises principally from vigorous active transport of NaCl, without accompanying water, from the thick ascending limbs of short- and long-looped nephrons. The tubule fluid of the thick limbs that enters the cortex is diluted well below plasma osmolality, and thus, the requirement of mass balance is met. In rats and mice, the thick limbs are localized near the collecting ducts ; mathematical models suggest that at a given level of the outer medulla, the interstitial osmolality will be higher near the collecting ducts than near the vascular bundles. This higher osmolality will facilitate water withdrawal from the descending limbs of long loops and from collecting ducts. Descending vasa recta are thought to be found only in the vascular bundles. Thus the ascending vasa recta will act as the collectors of any NaCl that is absorbed from loops of Henle and water that is absorbed from the descending limbs of long loops and from collecting ducts.

The countercurrent configuration of the ascending vasa recta, relative to the descending limbs and collecting ducts, is likely to participate in sustaining the axial gradient: as ascending vasa recta fluid ascends toward the cortex, its osmolality will exceed that in the descending limbs of long loops and in the collecting ducts. Thus ascending vasa recta fluid will be progressively diluted as that fluid contributes to the concentrating of fluid in descending limbs of long loops and in collecting ducts, by giving up NaCl to, and absorbing water from, the interstitium ( Figure 10.10 ).

Outer medullary concentrating mechanism based on NaCl addition to the interstitium but without water absorption from descending limbs of short loops.

Arrows indicate water (cyan) and NaCl (yellow) transepithelial transport; arrow widths suggest relative transport magnitudes. Isotonic fluid is considered to have the same osmolality as blood plasma. Flow entering the ascending vas rectum (AVR) is assumed to arise from a descending vas rectum that is in, or near, a vascular bundle. Outflow from collecting duct (CD) enters the inner medullary CD. Tubule fluid flow direction is indicated by blue arrows ; increasing osmolality is indicated by darkening shades of blue . Thick blue lines indicate that a tubule is impermeable to water; thin lines indicate high permeability to water. IS, inner stripe; OS, Outer stripe.

The previous summary appears to account for the elevation of osmolality in the outer medulla without invoking a role for countercurrent multiplication. However, a question remains: why does the osmolality gradient increase along the outer medulla as a function of increasing medullary depth? The answer likely lies in the local balance of NaCl absorption from thick limbs and water absorption from descending limbs of long loops and from collecting ducts. At deeper medullary levels, the rate of NaCl absorption from thick limbs may be higher than at shallow levels, owing to a higher Na ⁺ -K ⁺ -ATPase activity at deeper levels and to a saturation of transport proteins by the higher NaCl concentration in thick limb tubule fluid before dilution. Moreover, because of the water already absorbed in the upper outer medulla, the load of water presented to the thick limbs deep in the outer medulla by descending limbs of long loops and by the collecting ducts is much reduced.

A caveat is in order. Our understanding of the outer medulla is mostly based on information obtained from heavily studied laboratory animals, especially rats and mice. Outer medullary function and structure are likely to vary substantially in other species. For example, the human kidney has limited concentrating capability (relative to many other mammals), and only approximately one seventh of the loops of Henle are long ; the mountain beaver (Aplodontia rufa) has mostly cortical loops of Henle and essentially no inner medulla. It seems likely that the outer medullary structure in these species differs substantially from that in rats and mice. Finally, it should be acknowledged that the paradigm formulated earlier is similar to that proposed by Berliner and coworkers in 1958.

Accumulation of Urea in the Renal Inner Medulla

Urea accumulation within the inner medulla is partly dependent on variable urea permeabilities along the collecting duct system ( Figure 10.11 ). Within the collecting duct system, only the terminal portion of the IMCD possesses high urea permeability, which can be further increased by vasopressin. The effects of vasopressin are mediated (at least in part) by the secondary messenger cyclic adenosine monophosphate (cAMP). Urea-specific transporters are localized to the apical and basolateral plasma membranes of the IMCD cells and are responsible for the high urea permeability of the terminal portion of the IMCD.

Urea permeabilities of mammalian renal tubule segments.

The width of each segment in the diagram is distorted to be proportional to the urea permeability of that segment. Numbers in parentheses are measured values for the permeability coefficient (× 10 ⁻⁵ cm/sec). Values are from isolated perfused tubule studies. ATL, Ascending thin limb; CCD, cortical collecting duct; CTAL, cortical thick ascending limb; IMCDi, initial inner medullary collecting duct; IMCDt, terminal inner medullary collecting duct; LDL, long-loop thin descending limb; MTAL, medullary thick ascending limb; OMCD, outer medullary collecting duct; PST, proximal straight tubule; SDL, short descending limb.

The mechanisms of urea accumulation in the renal medulla are depicted in Figure 10.12 . Accumulation of urea is predominantly a result of passive urea reabsorption from the IMCD. Tubule fluid entering the collecting duct system in the renal cortex has a relatively low urea concentration. However, during antidiuresis, water is osmotically reabsorbed from the urea-impermeable parts of the collecting duct system in the cortex and outer medulla, causing a progressive increase in the luminal urea concentration along the connecting tubules, cortical collecting ducts, and outer medullary collecting ducts. Thus, when the tubule fluid reaches the highly urea-permeable terminal IMCD (due to the presence of urea transporters), urea rapidly exits from the lumen to the inner medullary interstitium, where it is “trapped” by countercurrent urea exchange between descending and ascending flows in both vasa recta and loops of Henle. Under steady-state conditions, and in the continued presence of vasopressin, urea nearly equilibrates across the IMCD epithelium and thus osmotically balances the urea in the collecting duct lumen, preventing possible instances of osmotic diuresis ( Figure 10.13 ).

Schematic representation of the mammalian collecting duct system showing principal sites of water absorption and urea absorption.

Water is absorbed in the early part of the collecting duct system, driven by an osmotic gradient. Because urea permeabilities of the cortical collecting duct, outer medullary collecting duct, and initial inner medullary collecting duct (IMCD) are very low, the water absorption concentrates urea in the lumen of these segments. When the tubule fluid reaches the terminal IMCD, which is highly permeable to urea, urea rapidly exits from the lumen. This urea is trapped in the inner medulla as a result of countercurrent exchange.

Solutes that account for osmolality of medullary interstitium and tubule fluid in the inner medullary collecting duct (IMCD) during antidiuresis in rats.

Urea nearly equilibrates across the IMCD epithelium as a result of rapid facilitated urea transport. Although the osmolalities of the fluid in the two spaces are nearly equal, the nonurea solutes can differ considerably between the two compartments. Typical values in untreated rats are presented. Values can differ considerably in other species and in the same species with different diets. NUN, Nonurea nitrogen.

The descending and ascending vasa recta are in close association with each other in the inner medulla, facilitating countercurrent exchange of urea between the two structures. In the ascending vasa recta, aided by the extremely high (>40 × 10 ⁻⁵ cm/sec) permeability to urea, the concentration of urea exiting the inner medulla is similar to the concentration of urea in the descending vasa recta. This minimizes the washout of urea from the inner medulla. However, countercurrent exchange cannot completely eliminate loss of urea from the inner medullary interstitium, because the volume flow rate of blood in the ascending vasa recta exceeds that in the descending vasa recta. During antidiuresis, water is added to the vasa recta from both IMCDs and descending limbs, resulting in a higher volume flow rate and an increased mass flow rate of urea. This ensures that the inner medullary vasculature continually removes urea from the inner medulla. Quantitatively, the most important loss of urea from the inner medullary interstitium is thought to occur via the vasa recta, but urea recycling pathways play a major role in limiting the loss of urea from the inner medulla. These pathways have been further elucidated via the use of knockout mouse models (see later). Three major urea recycling pathways are described in the following list, and an overview of these is shown in Figure 10.14 .

• 1.
  

  Recycling of urea through the ascending limbs, distal tubules, and collecting ducts. Urea that escapes the inner medulla in the ascending limbs of the long loops of Henle is carried back through the thick ascending limbs, DCTs, and early portions of the collecting duct system by the flow of tubule fluid. When it reaches the urea-permeable part of the IMCDs, it passively exits into the inner medullary interstitium and starts the cycle again.

  
  
• 2.
  

  Recycling of urea through the vasa recta, short loops of Henle, and collecting ducts. The delivery of urea to the superficial distal tubule exceeds the delivery out of the superficial proximal tubule. This implies that net urea addition occurs somewhere along the short loops of Henle. One possible mechanism is that the urea leaving the inner medulla in the vasa recta is transferred to the descending limbs of the short loops of Henle and is subsequently carried through the superficial distal tubules back to the urea-permeable part of the IMCDs, where it passively exits, completing the recycling pathway. The close physical association between the vasa recta and the descending limbs of the short loops in the vascular bundles of the inner stripe of the outer medulla would facilitate this transfer of urea from the vasa recta to the short loops of Henle. Furthermore, the existence of a facilitative urea transporter, UT-A2, in the thin descending limb of the short loops of Henle provides further support for this mechanism. However, later studies on UT-A2 knockout mice and UT-A2/UT-B knockout mice have raised doubts about the importance of this pathway.

  
  
• 3.
  

  Urea recycling between ascending and descending limbs of the loops of Henle. The urea permeability of thick ascending limbs from the inner stripe of the outer medulla is low. However, the urea permeability of thick ascending limbs from the outer stripe of the outer medulla and the medullary rays is relatively high. Based on this, a urea recycling pathway has been proposed in which urea is reabsorbed from thick ascending limbs and is secreted into neighboring proximal straight tubules, forming a recycling pathway between the ascending limbs and the descending limbs of the loop of Henle. Urea recycling from the thick ascending limbs and the proximal straight tubules is facilitated by the parallel relationship of these two structures in the outer stripe of the outer medulla and in the medullary rays. This transfer of urea is also likely to depend on a relatively attenuated effective blood flow in these regions. Urea secretion into the proximal straight tubules can occur by passive diffusion, active transport, or a combination of both. Urea presumably enters the proximal straight tubules of both short- and long-looped nephrons. The urea that enters the short-looped nephrons will be carried back to the inner medulla by the flow of tubule fluid through the superficial distal tubules and cortical collecting ducts, reentering the inner medullary interstitium by reabsorption from the terminal IMCD. The urea that enters proximal straight tubules of long-looped nephrons returns to the inner medulla directly through the descending limbs of the loops of Henle.

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