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Molecular Physiology of the Medullary Collecting Duct

Robert A. Fenton, Jeppe Praetorius

10.1002/cphy.c100064

Source: Volume 1, Issue 2, April 2011

Published online: April 2011

Full Article on Wiley Online Library



Abstract

The mammalian kidney is responsible for a multitude of homeostatic functions, which are mediated by both structural and functional diversity along the renal tubule. In this article, we focus on the major functions of the terminal portion of the renal tubule, the medullary collecting duct system. The role of the medullary collecting ducts in determining the composition of the final urine through controlled water, sodium, chloride, potassium and urea reabsorption, ammonia transport, and acid‐base homeostasis is discussed. The molecular identity of the major channels and transporters that contribute to medullary collecting duct function are described in detail, including; aquaporins, urea transporters, the epithelial sodium channel (ENaC), the Na,K‐ATPase, H‐ATPase, Rh glycoproteins, and sodium bicarbonate transporters. Knowledge gained from studies in knockout mice is also discussed. © 2011 American Physiological Society. Compr Physiol 1:1031‐1056, 2011.

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Figure 1. Figure 1.

Schematic representation of the mammalian renal tubule, with both long‐looped and short‐loop nephrons depicted. Major regions of the kidney are shown on the left. The regions are; proximal tubule (blue), thin limbs of Henle's loop (single thin line), thick ascending limb of Henle's loop (red), distal convoluted tubule (green), and the collecting duct (yellow).
Figure 2. Figure 2.

Urine flow in the terminal inner medullary collecting ducts (IMCD) and renal pelvis. Urine exits the IMCD through the ducts of Bellini at the tip of the renal papilla. Some urine can reflux backwards into the pelvic space.
Figure 3. Figure 3.

(A) Five primary clusters making up a single secondary collecting duct (CD) cluster that consists of 31 CDs at the IM base. Image shows section 400 μm below inner medulla base. CD cluster boundaries (white) were determined by an Euclidean distance map (EDM). Magenta, descending thin limb (DTL)/aquaporin‐1 (AQP1); blue, CD/AQP‐2; green, ascending thin limb (ATL)/kidney‐specific Cl− channel (ClC‐K1). Scale bar, 100 μm. (B) Inner medullary section showing 23 primary CD clusters with boundaries determined by EDM (white outlines). EDM boundaries around each CD are shown in gray. Image is an overlay of two images from two sections ∼400 μm below the IM base. Red, DTL/AQP1; blue, CD/AQP‐2; green, DVR/UT‐B. Scale bar, 500 μm. Figure adapted from 201 with permission
Figure 4. Figure 4.

Urea permeabilities of mammalian renal tubule segments. The width of each segment is proportional to the urea permeability of that segment, Values are from isolated perfused tubule studies 44,233,235.
Figure 5. Figure 5.

(A) Transmission electron micrograph (TEM) of a principal cell from the initial portion of the rat IMCD. Few organelles are detected in the cytoplasm, and apical microprojections are sparse (×11,750). Adapted from 170 with permission. (B) TEM of an OMCD intercalated cell. Extensive apical microprojections are apparent (×10,000). Adapted from 171 with permission. (C) Scanning electron micrograph of papillary collecting duct from rabbit demonstrates the junction between two collecting ducts (×600). Adapted from 141 with permission. (D) TEM of cells from the terminal IMCD. Cells are tall, with few organelles and sparse apical microprojections (×7000). Adapted from 170 with permission
Figure 6. Figure 6.

Water permeability of the mammalian renal tubule. Left; configuration of a long‐looped nephron showing the various tubule segments. Right; osmotic water permeability (pf, um/s) of the different regions under either control (basal) or after AVP stimulation. Data from 197.
Figure 7. Figure 7.

Immunofluorescence microscopy of AQP‐2 in cortical (A), outer medullary (B), and inner medullary (C and D) collecting duct and of AQP3 (E) and AQP‐4 (F) in inner medullary collecting duct (IMCD). AQP‐2 is very abundant in the apical plasma membrane domains as well as in subapical domains (arrows in A, B, and D), whereas intercalated cells are unlabeled (arrowheads in A and B). In the IMCD, AQP‐2 is also present in the basolateral part of the cell. AQP3 is abundant in both basal and lateral plasma membranes, whereas AQP‐4 is predominantly expressed in the basal plasma membrane and less prominently in the lateral plasma membranes. Magnification: ×1100 (A, B, D‐F) and ×550 (C). From 196, as reprinted in 194. Used with permission
Figure 8. Figure 8.

Percentage reabsorption of filtered NaCl along the nephron. Tubule depicted as in Figure 1. NaCl reabsorption in the medullary collecting duct is influenced by various factors that either stimulate (+) or inhibit (−) Na+ reabsorption. AVP, arginine vasopressin; MC, mineralocorticoids; BK, bradykinin; PGE2, prostaglandin E2; ET, endothelin.
Figure 9. Figure 9.

Urea handling in mammals. The majority of mammals consume diets that are high in protein. Under most circumstances, this dietary protein intake greatly exceeds that which is necessary for the support of anabolic processes. Excess protein is catabolized by the liver, which results in the formation of large amounts of urea by the ornithine‐urea cycle. Urea is freely filterable by the kidney and the excretion of this urea constitutes a large osmotic load to the kidney. Most solutes excreted in such large amounts would obligate large amounts of water excretion by causing an osmotic diuresis. However, along the nephron, the specialized urea transporters UT‐A1, UT‐A2, UT‐A3, and UT‐B are involved in complex urea reabsorption and recycling pathways that allow large amounts of urea to be excreted without obligating water excretion. Figure is adapted from 75, with permission
Figure 10. Figure 10.

Schematic of the collecting duct system showing principal sites of water absorption and urea absorption. Water is absorbed in early part of the collecting duct system driven by an osmotic gradient. Since the urea permeability of cortical collecting ducts, outer medullary collecting ducts and initial IMCDs 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.
Figure 11. Figure 11.

(A) Corticomedullary NH4+ gradients in canine renal medulla. NH4+ concentrations were measured in tissue water from slices from cortex and medulla of untreated dogs. Data plotted from 218. (B) Countercurrent multiplier for NH4+ in renal medulla. Active absorption of NH4+ from thick ascending limb of loop of Henle provides a single effect for countercurrent multiplication. Modified from 100 with permission
Figure 12. Figure 12.

Spatial distribution of different aquaporins, urea transporters, ion transporters/channels and enzymes, each with a specialized role in regulating the homeostatic functions of the kidney.
Figure 13. Figure 13.

Spatial distribution of different aquaporins, urea transporters, ion transporters/channels and enzymes, each with a specialized role in regulating the homeostatic functions of the kidney.
Figure 14. Figure 14.

The AQP‐4 M23 isoform forms square arrays in Xenopus laevis oocytes. (A‐C) At the plasma membrane, highly ordered structures characteristic of square arrays are observed for the AQP‐4 M23 isoform. Figure adapted from 79 with permission
Figure 15. Figure 15.

Water conservation and urinary concentrating ability of UT‐A1/3 knockout mice. For all graphs, data are means ± SEM; wild‐type mice are indicated by solid lines, and knockout mice are represented by dashed lines. Graphs show either the urine output under basal conditions (free access to drinking water) for 3 consecutive days, followed by a 24‐h water restriction on a 4% (A), 20% (B), or 40% (C) protein diet. The conclusion from these data is that the role of IMCD urea transporters in water conservation is to prevent a urea‐induced osmotic diuresis. Adapted from data in references 73,75.


Figure 1.

Schematic representation of the mammalian renal tubule, with both long‐looped and short‐loop nephrons depicted. Major regions of the kidney are shown on the left. The regions are; proximal tubule (blue), thin limbs of Henle's loop (single thin line), thick ascending limb of Henle's loop (red), distal convoluted tubule (green), and the collecting duct (yellow).



Figure 2.

Urine flow in the terminal inner medullary collecting ducts (IMCD) and renal pelvis. Urine exits the IMCD through the ducts of Bellini at the tip of the renal papilla. Some urine can reflux backwards into the pelvic space.



Figure 3.

(A) Five primary clusters making up a single secondary collecting duct (CD) cluster that consists of 31 CDs at the IM base. Image shows section 400 μm below inner medulla base. CD cluster boundaries (white) were determined by an Euclidean distance map (EDM). Magenta, descending thin limb (DTL)/aquaporin‐1 (AQP1); blue, CD/AQP‐2; green, ascending thin limb (ATL)/kidney‐specific Cl− channel (ClC‐K1). Scale bar, 100 μm. (B) Inner medullary section showing 23 primary CD clusters with boundaries determined by EDM (white outlines). EDM boundaries around each CD are shown in gray. Image is an overlay of two images from two sections ∼400 μm below the IM base. Red, DTL/AQP1; blue, CD/AQP‐2; green, DVR/UT‐B. Scale bar, 500 μm. Figure adapted from 201 with permission



Figure 4.

Urea permeabilities of mammalian renal tubule segments. The width of each segment is proportional to the urea permeability of that segment, Values are from isolated perfused tubule studies 44,233,235.



Figure 5.

(A) Transmission electron micrograph (TEM) of a principal cell from the initial portion of the rat IMCD. Few organelles are detected in the cytoplasm, and apical microprojections are sparse (×11,750). Adapted from 170 with permission. (B) TEM of an OMCD intercalated cell. Extensive apical microprojections are apparent (×10,000). Adapted from 171 with permission. (C) Scanning electron micrograph of papillary collecting duct from rabbit demonstrates the junction between two collecting ducts (×600). Adapted from 141 with permission. (D) TEM of cells from the terminal IMCD. Cells are tall, with few organelles and sparse apical microprojections (×7000). Adapted from 170 with permission



Figure 6.

Water permeability of the mammalian renal tubule. Left; configuration of a long‐looped nephron showing the various tubule segments. Right; osmotic water permeability (pf, um/s) of the different regions under either control (basal) or after AVP stimulation. Data from 197.



Figure 7.

Immunofluorescence microscopy of AQP‐2 in cortical (A), outer medullary (B), and inner medullary (C and D) collecting duct and of AQP3 (E) and AQP‐4 (F) in inner medullary collecting duct (IMCD). AQP‐2 is very abundant in the apical plasma membrane domains as well as in subapical domains (arrows in A, B, and D), whereas intercalated cells are unlabeled (arrowheads in A and B). In the IMCD, AQP‐2 is also present in the basolateral part of the cell. AQP3 is abundant in both basal and lateral plasma membranes, whereas AQP‐4 is predominantly expressed in the basal plasma membrane and less prominently in the lateral plasma membranes. Magnification: ×1100 (A, B, D‐F) and ×550 (C). From 196, as reprinted in 194. Used with permission



Figure 8.

Percentage reabsorption of filtered NaCl along the nephron. Tubule depicted as in Figure 1. NaCl reabsorption in the medullary collecting duct is influenced by various factors that either stimulate (+) or inhibit (−) Na+ reabsorption. AVP, arginine vasopressin; MC, mineralocorticoids; BK, bradykinin; PGE2, prostaglandin E2; ET, endothelin.



Figure 9.

Urea handling in mammals. The majority of mammals consume diets that are high in protein. Under most circumstances, this dietary protein intake greatly exceeds that which is necessary for the support of anabolic processes. Excess protein is catabolized by the liver, which results in the formation of large amounts of urea by the ornithine‐urea cycle. Urea is freely filterable by the kidney and the excretion of this urea constitutes a large osmotic load to the kidney. Most solutes excreted in such large amounts would obligate large amounts of water excretion by causing an osmotic diuresis. However, along the nephron, the specialized urea transporters UT‐A1, UT‐A2, UT‐A3, and UT‐B are involved in complex urea reabsorption and recycling pathways that allow large amounts of urea to be excreted without obligating water excretion. Figure is adapted from 75, with permission



Figure 10.

Schematic of the collecting duct system showing principal sites of water absorption and urea absorption. Water is absorbed in early part of the collecting duct system driven by an osmotic gradient. Since the urea permeability of cortical collecting ducts, outer medullary collecting ducts and initial IMCDs 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.



Figure 11.

(A) Corticomedullary NH4+ gradients in canine renal medulla. NH4+ concentrations were measured in tissue water from slices from cortex and medulla of untreated dogs. Data plotted from 218. (B) Countercurrent multiplier for NH4+ in renal medulla. Active absorption of NH4+ from thick ascending limb of loop of Henle provides a single effect for countercurrent multiplication. Modified from 100 with permission



Figure 12.

Spatial distribution of different aquaporins, urea transporters, ion transporters/channels and enzymes, each with a specialized role in regulating the homeostatic functions of the kidney.



Figure 13.

Spatial distribution of different aquaporins, urea transporters, ion transporters/channels and enzymes, each with a specialized role in regulating the homeostatic functions of the kidney.



Figure 14.

The AQP‐4 M23 isoform forms square arrays in Xenopus laevis oocytes. (A‐C) At the plasma membrane, highly ordered structures characteristic of square arrays are observed for the AQP‐4 M23 isoform. Figure adapted from 79 with permission



Figure 15.

Water conservation and urinary concentrating ability of UT‐A1/3 knockout mice. For all graphs, data are means ± SEM; wild‐type mice are indicated by solid lines, and knockout mice are represented by dashed lines. Graphs show either the urine output under basal conditions (free access to drinking water) for 3 consecutive days, followed by a 24‐h water restriction on a 4% (A), 20% (B), or 40% (C) protein diet. The conclusion from these data is that the role of IMCD urea transporters in water conservation is to prevent a urea‐induced osmotic diuresis. Adapted from data in references 73,75.

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Article Title: Molecular Physiology of the Medullary Collecting Duct
 

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Robert A. Fenton, Jeppe Praetorius. Molecular Physiology of the Medullary Collecting Duct. Compr Physiol 2011, 1: 1031-1056. doi: 10.1002/cphy.c100064