Role Of NH3 And NH4+ Transporters In Renal Acid-base ... - PubMed

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Abstract

Renal ammonia excretion is the predominant component of renal net acid excretion. The majority of ammonia excretion is produced in the kidney and then undergoes regulated transport in a number of renal epithelial segments. Recent findings have substantially altered our understanding of renal ammonia transport. In particular, the classic model of passive, diffusive NH3 movement coupled with NH4+ "trapping" is being replaced by a model in which specific proteins mediate regulated transport of NH3 and NH4+ across plasma membranes. In the proximal tubule, the apical Na+/H+ exchanger, NHE-3, is a major mechanism of preferential NH4+ secretion. In the thick ascending limb of Henle's loop, the apical Na+-K+-2Cl- cotransporter, NKCC2, is a major contributor to ammonia reabsorption and the basolateral Na+/H+ exchanger, NHE-4, appears to be important for basolateral NH4+ exit. The collecting duct is a major site for renal ammonia secretion, involving parallel H+ secretion and NH3 secretion. The Rhesus glycoproteins, Rh B Glycoprotein (Rhbg) and Rh C Glycoprotein (Rhcg), are recently recognized ammonia transporters in the distal tubule and collecting duct. Rhcg is present in both the apical and basolateral plasma membrane, is expressed in parallel with renal ammonia excretion, and mediates a critical role in renal ammonia excretion and collecting duct ammonia transport. Rhbg is expressed specifically in the basolateral plasma membrane, and its role in renal acid-base homeostasis is controversial. In the inner medullary collecting duct (IMCD), basolateral Na+-K+-ATPase enables active basolateral NH4+ uptake. In addition to these proteins, several other proteins also contribute to renal NH3/NH4+ transport. The role and mechanisms of these proteins are discussed in depth in this review.

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Figures

Fig. 1.

Fig. 1.

Model of NH 3 . …

Fig. 1.

Model of NH 3 . A : space-filling model of the atomic structure…

Fig. 1. Model of NH3. A: space-filling model of the atomic structure of NH3 that demonstrates the asymmetric distribution of hydrogen nuclei (H) surrounding the central nitrogen (N). B: electrostatic charge distribution of NH3. A positive charge (blue) is concentrated near the hydrogen nuclei, and a negative charge (red) is concentrated adjacent to the nitrogen.
Fig. 2.

Fig. 2.

Ammonia production in various renal…

Fig. 2.

Ammonia production in various renal segments: basal and acidosis-stimulated rates. Ammonia production rates…

Fig. 2. Ammonia production in various renal segments: basal and acidosis-stimulated rates. Ammonia production rates in different renal components were measured in microdissected epithelial cell segments from rats on control diets and after induction of metabolic acidosis. All segments tested produced ammonia. Metabolic acidosis increased total renal ammoniagenesis, but only through increased production in proximal tubule segments (S1, S2, and S3). Rates were calculated from measured ammonia production rates and mean length per segment as described (37). DTL, descending thin limb of Henle's loop; mTAL, medullary thick ascending limb of Henle's loop; cTAL, cortical thick ascending limb of Henle's lop; DCT, distal convoluted tubule; CCD, cortical collecting duct; OMCD, outer medullary collecting duct; IMCD, inner medullary collecting duct.
Fig. 3.

Fig. 3.

Ammonia transport along the various…

Fig. 3.

Ammonia transport along the various renal epithelial segments. Ammonia is primarily produced in…

Fig. 3. Ammonia transport along the various renal epithelial segments. Ammonia is primarily produced in the proximal tubule. It is preferentially secreted into the luminal fluid through mechanisms which involve NHE-3-mediated Na+/NH4+ exchange, NH4+ transport through Ba2+-inhibitable K+ channels, and an uncharacterized NH3 transport pathway. Ammonia is reabsorbed by the TAL through a process primarily involving Na+-K+-2Cl− cotransporter (NKCC2)-mediated NH4+ reabsorption. Recycling of ammonia through secretion in the DTL results in ammonia delivery to the turn of the loop of Henle that exceeds total excreted ammonia. NH4+ reabsorption in the TAL, however, results in total ammonia delivery to distal nephron segments that accounts for only a minority of total excreted ammonia. Ammonia secretion in the collecting duct involves parallel H+ and NH3 secretion. Numbers in blue reflect proportion of total urinary ammonia delivered to indicated sites. Specific details of ammonia secretion in each of these nephron segments are provided in the text.
Fig. 4.

Fig. 4.

Ammonia transport in the proximal…

Fig. 4.

Ammonia transport in the proximal tubule. Ammonia is produced in the proximal tubule…

Fig. 4. Ammonia transport in the proximal tubule. Ammonia is produced in the proximal tubule primarily from metabolism of glutamine and occurs primarily in the mitochondria. The enzymatic details of ammoniagenesis are not shown. Three transport mechanisms appear to mediate preferential apical ammonia secretion. These include Na+/NH4+ exchange via NHE-3, parallel NH3 secretion and NHE-3-mediated Na+/H+ exchange, and a Ba2+-sensitive NH4+ conductance likely mediated by apical K+ channels. HCO3− is produced in equimolar amounts as NH4+ in the process of ammoniagenesis and is primarily transported across the basolateral plasma membrane by NBCe1. Minor components of basolateral NH4+ uptake via Na+-K+-ATPase and by basolateral K+ channels are not shown.
Fig. 5.

Fig. 5.

Ammonia reabsorption in the TAL.…

Fig. 5.

Ammonia reabsorption in the TAL. The primary mechanism of ammonia reabsorption in the…

Fig. 5. Ammonia reabsorption in the TAL. The primary mechanism of ammonia reabsorption in the TAL is via substitution of NH4+ for K+ and transport by NKCC2. Electroneutral K+/NH4+ exchange and conductive K+ transport are also present, but are quantitatively less significant components of apical K+ transport. Diffusive NH3 transport across the apical plasma membrane is present, but is not quantitatively significant. Cytosolic NH4+ can exit via basolateral NHE-4. A second mechanism of basolateral NH4+ exit may involve dissociation to NH3 and H+, with NH3 exit via an uncharacterized, presumably diffusive, mechanism and buffering of intracellular H+ released via sodium-bicarbonate cotransporter NBCn1-mediated HCO3− entry.
Fig. 6.

Fig. 6.

Model of collecting duct ammonia…

Fig. 6.

Model of collecting duct ammonia secretion. In the interstitium, NH 4 + is…

Fig. 6. Model of collecting duct ammonia secretion. In the interstitium, NH4+ is in equilibrium with NH3 and H+. NH3 is transported across the basolateral membrane through both Rhesus glycoproteins Rhbg and Rhcg. In the IMCD, basolateral Na+-K+-ATPase is a major mechanism of basolateral NH4+ uptake, followed by dissociation of NH4+ to NH3 and H+ (grey lines). Intracellular NH3 is secreted across the apical membrane by apical Rhcg. H+ secreted by H+-ATPase and H+-K+-ATPase combine with luminal NH3 to form NH4+, which is “trapped” in the lumen. In addition, there may also be minor components of diffusive NH3 movement across both the basolateral and apical plasma membranes (dotted lines). The intracellular H+ that is secreted by H+-ATPase and H+-K+-ATPase is generated by carbonic anhydrase (CA) II-accelerated CO2 hydration that forms carbonic acid, which dissociates to H+ and HCO3−. Basolateral Cl−/HCO3− exchange transports HCO3− across the basolateral membrane; HCO3− combines with H+ released from NH4+, to form carbonic acid, which dissociates to CO2 and water. This CO2 can recycle into the cell, supplying the CO2 used for cytosolic H+ production. The net result is NH4+ transport from the peritubular space into the luminal fluid. In the non-A, non-B cell, which lacks substantial basolateral Rhcg expression, Rhbg is likely the primary basolateral NH3 transport mechanism. The B-type intercalated cell, which lacks detectable Rhbg and Rhcg expression, likely mediates transcellular ammonia secretion through mechanisms only involving lipid-phase NH3 diffusion and thus transports ammonia at significantly slower rates.
Fig. 7.

Fig. 7.

Expression of Rhbg and Rhcg…

Fig. 7.

Expression of Rhbg and Rhcg in different intercalated cell populations. The expression and…

Fig. 7. Expression of Rhbg and Rhcg in different intercalated cell populations. The expression and localization of Rhbg and Rhcg differ in the type A, type B, and non-A, non-B intercalated cells. The type A intercalated cell, characterized by apical H+-ATPase and basolateral AE1, expresses apical and basolateral Rhcg and basolateral Rhbg. The type B intercalated cell, characterized by apical pendrin and basolateral H+-ATPase, does not express either Rhbg or Rhcg detectable by immunohistochemistry. The non-A, non-B intercalated cell, characterized by apical pendrin and apical H+-ATPase, expresses apical, but not basolateral, Rhcg and expresses basolateral Rhbg. This figure is based on a drawing originally prepared by Dr. Ki-Hwan Han.
Fig. 8.

Fig. 8.

Molecular structure of human RhCG…

Fig. 8.

Molecular structure of human RhCG showing key residues. A : ribbon structure model…

Fig. 8. Molecular structure of human RhCG showing key residues. A: ribbon structure model with lateral view. Twin, coplanar histidine residues, His185 and His344, function to stabilize NH3 transport and provide selectivity relative to other solutes, such as NH4, and are shown in ball-and-stick representation. Acidic residues in extracellular and intracellular vestibules, function in NH4+ attraction and stabilization (Glu166, Asp218, Asp278, and Glu329), and are shown in space-filling representation. B: cytoplasmic view of channel, demonstrating key NH4+-stabilizing acidic residues (Asp218, Asp278, and Glu329), coplanar histidine residues in pore channel, and representation of extracellular vestibule acidic residue (Glu166). Models were generated using BallView software, version 1.3.2 using human RhCG data (3HD6).
All figures (8) See this image and copyright information in PMC

References

    1. Ambuhl PM, Amemiya M, Danczkay M, Lotscher M, Kaissling B, Moe OW, Preisig PA, Alpern RJ. Chronic metabolic acidosis increases NHE3 protein abundance in rat kidney. Am J Physiol Renal Fluid Electrolyte Physiol 271: F917–F925, 1996 - PubMed
    1. Amemiya M, Loffing J, Lotscher M, Kaissling B, Alpern RJ, Moe OW. Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney Int 48: 1206–1215, 1996 - PubMed
    1. Andrade SLA, Dickmanns A, Ficner R, Einsle O. Crystal structure of the archaeal ammonium transporter Amt-1 from Archaeoglobus fulgidus. Proc Natl Acad Sci USA 102: 14994–14999, 2005 - PMC - PubMed
    1. Aronson PS, Suhm MA, Nee J. Interaction of external H+ with the Na+-H+ exchanger in renal microvillus membrane vesicles. J Biol Chem 258: 6767–6711, 1983 - PubMed
    1. Atkins PW. Molecules in motion: ion transport and molecular diffusion. In: Physical Chemistry, edited by Atkins PW. Oxford, UK: Oxford University Press, 1978, p. 819–848
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