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Urea Transport in the Kidney

Janet D. Klein, Mitsi A. Blount, Jeff M. Sands

10.1002/cphy.c100030

Source: Volume 1, Issue 2, April 2011

Published online: April 2011

Full Article on Wiley Online Library



Abstract

Urea transport proteins were initially proposed to exist in the kidney in the late 1980s when studies of urea permeability revealed values in excess of those predicted by simple lipid‐phase diffusion and paracellular transport. Less than a decade later, the first urea transporter was cloned. Currently, the SLC14A family of urea transporters contains two major subgroups: SLC14A1, the UT‐B urea transporter originally isolated from erythrocytes; and SLC14A2, the UT‐A group with six distinct isoforms described to date. In the kidney, UT‐A1 and UT‐A3 are found in the inner medullary collecting duct; UT‐A2 is located in the thin descending limb, and UT‐B is located primarily in the descending vasa recta; all are glycoproteins. These transporters are crucial to the kidney's ability to concentrate urine. UT‐A1 and UT‐A3 are acutely regulated by vasopressin. UT‐A1 has also been shown to be regulated by hypertonicity, angiotensin II, and oxytocin. Acute regulation of these transporters is through phosphorylation. Both UT‐A1 and UT‐A3 rapidly accumulate in the plasma membrane in response to stimulation by vasopressin or hypertonicity. Long‐term regulation involves altering protein abundance in response to changes in hydration status, low protein diets, adrenal steroids, sustained diuresis, or antidiuresis. Urea transporters have been studied using animal models of disease including diabetes mellitus, lithium intoxication, hypertension, and nephrotoxic drug responses. Exciting new animal models are being developed to study these transporters and search for active urea transporters. Here we introduce urea and describe the current knowledge of the urea transporter proteins, their regulation, and their role in the kidney. © 2011 American Physiological Society. Compr Physiol 1:699‐729, 2011.

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Figure 1. Figure 1.

(A) Structure of the nephron. The cartoon depicts the cortex (top), outer medulla (middle), and inner medulla (bottom) showing the location of the various substructures of the nephron labeled as follows: 1, glomerulus; 2, proximal convoluted tubule (PCT); 3s and 3l, proximal straight tubule (PST) in the short‐looped nephron (s) and long‐looped nephron (l); 4s and 4l, thin descending limb (tDL); 5, thin ascending limb (tAL); 6s and 6l, medullary thick ascending limb (mTAL); 7, macula densa; 8, distal convoluted tubule (DCT); 9, cortical collecting duct (CCD); 10, outer medullary collecting duct (OMCD); 11, initial inner medullary collecting duct (IMCD) and 12, terminal IMCD. (B) Urea permeabilities in the different nephron sections of rat kidney. Numbers correspond to areas identified in panel A.
Figure 2. Figure 2.

Cartoon showing the locations of the chief urea transporters (UT‐A1, UT‐A2, and UT‐A3), aquaporins (AQP2‐4) and sodium/potassium transporters (NKCC2, ROMK) in the nephron that contribute to concentration of the urine.
Figure 3. Figure 3.

Genomic organization (A) and gene products (B) of the rat Slc14aC gene. (A) The gene comprises 24 exons, of which the coding exons (red) and untranslated exons (blue) are drawn to scale. Introns <5 kb are also drawn to scale. Introns >5 kb are denoted by //. Triangles denote the α and β promoters. (B) Splicing patterns are shown for four characterized transcripts, UT‐A1, UT‐A2, UT‐A3, and UT‐A4. Coding exons (red) and untranslated exons (blue) are drawn to scale. Figure is adapted from Smith and Fenton 323.
Figure 4. Figure 4.

Comparison of the genomic organization of the urea transporter UT‐A gene (Slc14a2) for human, rat, and mouse. Above are schematic representations of the gene structure for each species. Exon width is representative of actual size and intronic distance is scaled. Introns >5 kb are represented by // and are not scaled. Triangles denote the α (purple) and β (pink) promoters. Coding exons (red) and untranslated exons (blue) are drawn to scale. Figure is adapted from Smith and Fenton 323.
Figure 5. Figure 5.

Secondary structure of human UT‐A1 based on theoretical extrapolation of the primary amino acid sequence. Individual amino acids are identified in bead form. Pink identifies acidic amino acids, blue are basic amino acids, green are the extracellular glycosylation sites at Asn 279 and Asn 742, and red shows the PKA phosphorylated serines at 477 and 490. Amino and carboxy termini are cytoplasmic and the structure indicates 12 membrane‐spanning domains.
Figure 6. Figure 6.

Crystal structure of bacterial urea transporter. Shown is a ribbon diagram of the proposed structure of the dvUT, reproduced by the kind permission of Macmillan Publishers and Nature 196. Dashed lines delineate the monomers. Arrows indicate entry points for urea in each monomer of the trimeric structure. Triangle is the axis of symmetry.
Figure 7. Figure 7.

UT‐A1 protein structure and cellular location. Panel A shows a schematic representation of the structure of UT‐A1 situated across the apical membrane. The schematic projects intracellular and extracellular loop regions, intracellular amino‐ and carboxy‐termini, and external glycosylation sites. Panel B is a thin (1 μ) section of rat kidney inner medulla stained with antibody to the carboxy terminus of UT‐A1 showing apical distribution of UT‐A1 in the tubule lumen. The micrograph was acquired at a 40× magnification.
Figure 8. Figure 8.

UT‐A2 protein structure and cellular location. Panel A shows a schematic representation of the structure of UT‐A2. The schematic projects intracellular and extracellular loop regions, intracellular amino‐ and carboxy‐termini, and external glycosylation sites. UT‐A2 is essentially the carboxy terminal half of UT‐A1 with only a small portion of the large intracellular loop region. Panel B is a thin (2 μ) section of rat kidney outer medulla stained with antibody to the carboxy terminus of UT‐A1 showing UT‐A2 in the thin limbs. The micrograph was acquired at a 40× magnification.
Figure 9. Figure 9.

UT‐A3 protein structure and cellular location. Panel A shows a schematic representation of the structure of UT‐A3 situated across the basal membrane. The schematic projects intracellular and extracellular loop regions, intracellular amino‐ and carboxy‐termini, and external glycosylation sites. Panel B is a thin (1 μ) section of rat kidney inner medulla stained with antibody that specifically recognizes UT‐A3 showing basal distribution of UT‐A3 in the tubule lumen. The micrograph was acquired at a 40× magnification.
Figure 10. Figure 10.

Urea transporter (UT‐A1) protein abundances in inner medullary (IM) base and tip of rats with diabetes mellitus (DM). Right: Western blots of IM tip (top) and base (Bottom) proteins. Both IM base and tip were probed with a specific antibody to UT‐A and show the characteristic 117‐ and 97‐kDa glycoprotein forms of UT‐A1. Within each gel, the left three lanes are control rat tissues, and the right three lanes are lysates from rats with DM. Each lane is tissue from a separate animal. Left: densitometric analysis of the total groups (n = 6) with combined 117‐ and 97‐kDa band densities averaged for each group expressed as % of control levels. Black portion of the bars represent the contribution of the 117 kDa glycoprotein form to the total density; white portions show the contribution of the 97 kDa glycoproteins. *, P < 0.05 for total UT‐A1 vs. control levels.
Figure 11. Figure 11.

Urea transporter (UT‐A1) protein abundances in inner medullary (IM) tip of rats fed a diet supplemented with lithium (40 mmol/kg of standard rat chow) for 0 (control), 7 days (7d), 14 days (14d), or fed the diet for 14 days, then had lithium removed for 7 days (7d r) or 14 days (14d r). Top: schematic of serum lithium levels. Middle: IM tip tissue probed with antibody to UT‐A1, 40× micrographs, brown indicates positive UT‐A1 presence in the IMCDs. Bottom: Western blots of IM tip probed for UT‐A1 protein abundance (top) and tubulin as a loading control (Bottom). Each lane is tissue from a separate animal.


Figure 1.

(A) Structure of the nephron. The cartoon depicts the cortex (top), outer medulla (middle), and inner medulla (bottom) showing the location of the various substructures of the nephron labeled as follows: 1, glomerulus; 2, proximal convoluted tubule (PCT); 3s and 3l, proximal straight tubule (PST) in the short‐looped nephron (s) and long‐looped nephron (l); 4s and 4l, thin descending limb (tDL); 5, thin ascending limb (tAL); 6s and 6l, medullary thick ascending limb (mTAL); 7, macula densa; 8, distal convoluted tubule (DCT); 9, cortical collecting duct (CCD); 10, outer medullary collecting duct (OMCD); 11, initial inner medullary collecting duct (IMCD) and 12, terminal IMCD. (B) Urea permeabilities in the different nephron sections of rat kidney. Numbers correspond to areas identified in panel A.



Figure 2.

Cartoon showing the locations of the chief urea transporters (UT‐A1, UT‐A2, and UT‐A3), aquaporins (AQP2‐4) and sodium/potassium transporters (NKCC2, ROMK) in the nephron that contribute to concentration of the urine.



Figure 3.

Genomic organization (A) and gene products (B) of the rat Slc14aC gene. (A) The gene comprises 24 exons, of which the coding exons (red) and untranslated exons (blue) are drawn to scale. Introns <5 kb are also drawn to scale. Introns >5 kb are denoted by //. Triangles denote the α and β promoters. (B) Splicing patterns are shown for four characterized transcripts, UT‐A1, UT‐A2, UT‐A3, and UT‐A4. Coding exons (red) and untranslated exons (blue) are drawn to scale. Figure is adapted from Smith and Fenton 323.



Figure 4.

Comparison of the genomic organization of the urea transporter UT‐A gene (Slc14a2) for human, rat, and mouse. Above are schematic representations of the gene structure for each species. Exon width is representative of actual size and intronic distance is scaled. Introns >5 kb are represented by // and are not scaled. Triangles denote the α (purple) and β (pink) promoters. Coding exons (red) and untranslated exons (blue) are drawn to scale. Figure is adapted from Smith and Fenton 323.



Figure 5.

Secondary structure of human UT‐A1 based on theoretical extrapolation of the primary amino acid sequence. Individual amino acids are identified in bead form. Pink identifies acidic amino acids, blue are basic amino acids, green are the extracellular glycosylation sites at Asn 279 and Asn 742, and red shows the PKA phosphorylated serines at 477 and 490. Amino and carboxy termini are cytoplasmic and the structure indicates 12 membrane‐spanning domains.



Figure 6.

Crystal structure of bacterial urea transporter. Shown is a ribbon diagram of the proposed structure of the dvUT, reproduced by the kind permission of Macmillan Publishers and Nature 196. Dashed lines delineate the monomers. Arrows indicate entry points for urea in each monomer of the trimeric structure. Triangle is the axis of symmetry.



Figure 7.

UT‐A1 protein structure and cellular location. Panel A shows a schematic representation of the structure of UT‐A1 situated across the apical membrane. The schematic projects intracellular and extracellular loop regions, intracellular amino‐ and carboxy‐termini, and external glycosylation sites. Panel B is a thin (1 μ) section of rat kidney inner medulla stained with antibody to the carboxy terminus of UT‐A1 showing apical distribution of UT‐A1 in the tubule lumen. The micrograph was acquired at a 40× magnification.



Figure 8.

UT‐A2 protein structure and cellular location. Panel A shows a schematic representation of the structure of UT‐A2. The schematic projects intracellular and extracellular loop regions, intracellular amino‐ and carboxy‐termini, and external glycosylation sites. UT‐A2 is essentially the carboxy terminal half of UT‐A1 with only a small portion of the large intracellular loop region. Panel B is a thin (2 μ) section of rat kidney outer medulla stained with antibody to the carboxy terminus of UT‐A1 showing UT‐A2 in the thin limbs. The micrograph was acquired at a 40× magnification.



Figure 9.

UT‐A3 protein structure and cellular location. Panel A shows a schematic representation of the structure of UT‐A3 situated across the basal membrane. The schematic projects intracellular and extracellular loop regions, intracellular amino‐ and carboxy‐termini, and external glycosylation sites. Panel B is a thin (1 μ) section of rat kidney inner medulla stained with antibody that specifically recognizes UT‐A3 showing basal distribution of UT‐A3 in the tubule lumen. The micrograph was acquired at a 40× magnification.



Figure 10.

Urea transporter (UT‐A1) protein abundances in inner medullary (IM) base and tip of rats with diabetes mellitus (DM). Right: Western blots of IM tip (top) and base (Bottom) proteins. Both IM base and tip were probed with a specific antibody to UT‐A and show the characteristic 117‐ and 97‐kDa glycoprotein forms of UT‐A1. Within each gel, the left three lanes are control rat tissues, and the right three lanes are lysates from rats with DM. Each lane is tissue from a separate animal. Left: densitometric analysis of the total groups (n = 6) with combined 117‐ and 97‐kDa band densities averaged for each group expressed as % of control levels. Black portion of the bars represent the contribution of the 117 kDa glycoprotein form to the total density; white portions show the contribution of the 97 kDa glycoproteins. *, P < 0.05 for total UT‐A1 vs. control levels.



Figure 11.

Urea transporter (UT‐A1) protein abundances in inner medullary (IM) tip of rats fed a diet supplemented with lithium (40 mmol/kg of standard rat chow) for 0 (control), 7 days (7d), 14 days (14d), or fed the diet for 14 days, then had lithium removed for 7 days (7d r) or 14 days (14d r). Top: schematic of serum lithium levels. Middle: IM tip tissue probed with antibody to UT‐A1, 40× micrographs, brown indicates positive UT‐A1 presence in the IMCDs. Bottom: Western blots of IM tip probed for UT‐A1 protein abundance (top) and tubulin as a loading control (Bottom). Each lane is tissue from a separate animal.

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Article Title: Urea Transport in the Kidney
 

How to Cite

Janet D. Klein, Mitsi A. Blount, Jeff M. Sands. Urea Transport in the Kidney. Compr Physiol 2011, 1: 699-729. doi: 10.1002/cphy.c100030