Role of NH3 and NHFormula transporters in renal acid-base transport

Division of Nephrology, Hypertension and Transplantation, University of Florida College of Medicine, Gainesville, FL 32610, USA.
AJP Renal Physiology (Impact Factor: 3.25). 11/2010; 300(1):F11-23. DOI: 10.1152/ajprenal.00554.2010
Source: PubMed


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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Available from: Jill W Verlander, May 01, 2015
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    • "In mammals, where renal ammonia excretion is necessary for maintaining acid–base balance (Knepper et al., 1989), there has been more attention to the specific mechanisms regulating ammonia flux. With the discovery of Rhesus (Rh) glycoproteins as ammonia transporters, the different transport proteins responsible for ammonia flux in different tubule segments have been partially identified (reviewed by Weiner and Verlander, 2011; Nakhoul and Lee Hamm, 2013; Weiner et al., 2013). For example, in the collecting duct, Rh glycoproteins (Rhbg, Rhcg) facilitate NH 3 diffusion and the blood–lumen NH 3 gradient is maintained by H + secretion via H + - ATPase and H + /K + -ATPase. "
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    ABSTRACT: Increased renal ammonia excretion in response to metabolic acidosis is thought to be a conserved response in vertebrates. We tested the hypothesis that Rhesus (Rh) glycoproteins in the kidney of the freshwater common carp Cyprinus carpio play a critical role in regulating renal ammonia excretion during chronic metabolic acidosis. Exposure to water pH 4.0 (72 h) resulted in a classic metabolic acidosis with reduced plasma pHa, [HCO3 (-)], no change in PCO2, and large changes in renal function. Urine [NH4 (+)] as well as [titratable acidity-HCO3 (-)] rose significantly over the acid exposure, but the profound reduction (5-fold) in urine flow rates eliminated the expected elevations in renal ammonia excretion. Low urine flow rates may be a primary strategy to conserve ions, as urinary excretion of Na(+), Cl(-) and Ca(2+) were significantly lower during the acid exposure relative to the control period. Interestingly, renal Rhcg1 mRNA and protein levels were elevated in acid relative to control groups, along with mRNA levels of several ion transporters, including the Na(+)/H(+) exchanger (NHE3), H(+)ATPase and Na(+)/K(+)ATPase (NKA). Immunofluorescence microscopy showed a strong apical Rhcg1 signal in distal tubules. Taken together, these data show that renal Rh glycoproteins and associated ion transporters are responsive to metabolic acidosis, but conservation of ions through reduced urine flow rates takes primacy over renal acid-base regulation in the freshwater C. carpio. We propose that an "acid/base-ion balance" compromise explains the variable renal responses to metabolic acidosis in freshwater teleosts.
    Journal of Experimental Biology 05/2014; 217(16). DOI:10.1242/jeb.098640 · 2.90 Impact Factor
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    • "The liver plays a major role in detoxifying the molecule into urea and glutamine, preventing its accumulation in the organism. In parallel, renal ammonium production and subsequent urinary elimination constitute an important process to maintain acid/base homeostasis [2]. The process is even more capital upon acid challenge, as generally happens with a classical Western acid diet [3], [4]. "
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    ABSTRACT: Proteins of the conserved Mep-Amt-Rh family, including mammalian Rhesus factors, mediate transmembrane ammonium transport. Ammonium is an important nitrogen source for the biosynthesis of amino acids but is also a metabolic waste product. Its disposal in urine plays a critical role in the regulation of the acid/base homeostasis, especially with an acid diet, a trait of Western countries. Ammonium accumulation above a certain concentration is however pathologic, the cytotoxicity causing fatal cerebral paralysis in acute cases. Alteration in ammonium transport via human Rh proteins could have clinical outcomes. We used a yeast-based expression assay to characterize human Rh variants resulting from non synonymous single nucleotide polymorphisms (nsSNPs) with known or unknown clinical phenotypes and assessed their ammonium transport efficiency, protein level, localization and potential trans-dominant impact. The HsRhAG variants (I61R, F65S) associated to overhydrated hereditary stomatocytosis (OHSt), a disease affecting erythrocytes, proved affected in intrinsic bidirectional ammonium transport. Moreover, this study reveals that the R202C variant of HsRhCG, the orthologue of mouse MmRhcg required for optimal urinary ammonium excretion and blood pH control, shows an impaired inherent ammonium transport activity. Urinary ammonium excretion was RHcg gene-dose dependent in mouse, highlighting MmRhcg as a limiting factor. HsRhCG(R202C) may confer susceptibility to disorders leading to metabolic acidosis for instance. Finally, the analogous R211C mutation in the yeast ScMep2 homologue also impaired intrinsic activity consistent with a conserved functional role of the preserved arginine residue. The yeast expression assay used here constitutes an inexpensive, fast and easy tool to screen nsSNPs reported by high throughput sequencing or individual cases for functional alterations in Rh factors revealing potential causal variants.
    PLoS ONE 08/2013; 8(8):e71092. DOI:10.1371/journal.pone.0071092 · 3.23 Impact Factor
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    • "Rh glycoproteins are expressed specifically in tissues in which ammonia transport is necessary for normal biological functioning. They are highly expressed in the kidneys, where ammonia formation and transport are central to renal regulation of acid–base homeostasis (Eladari et al. 2002, Quentin et al. 2003, Verlander et al. 2003, Weiner & Verlander 2011). In liver, Rh glycoproteins are expressed in perivenous hepatocytes, which mediate high-affinity ammonia metabolism (Weiner et al. 2003). "
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    ABSTRACT: The rhesus glycoproteins, Rh B glycoprotein (RHBG) and Rh C glycoprotein (RHCG), are recently identified ammonia transporters. Rhcg expression is necessary for normal male fertility, but its specific cellular expression is unknown, and Rhbg has not been reported to be expressed in the male reproductive tract. This study sought to determine the specific cellular expression of Rhcg, to determine whether Rhbg is expressed in the male reproductive tract, and, if so, to determine which cells express Rhbg using real-time RT-PCR, immunoblot analysis, and immunohistochemistry. Both Rhbg and Rhcg were expressed throughout the male reproductive tract. In the testis, high levels of Rhbg were expressed in Leydig cells, and Rhcg was expressed in spermatids during the later stages of their maturation (steps 13-16) in stages I-VIII of the seminiferous epithelium cycle. In the epididymis, basolateral Rhbg was present in narrow cells in the initial segment, in principal cells in the upper corpus, and in clear cells throughout the epididymis. Apical Rhcg immunolabel was present in principal cells in the caput and upper corpus epididymidis and in clear cells in the middle and lower corpus and cauda epididymidis. In the vas deferens, apical Rhcg immunolabel and basolateral Rhbg immunolabel were present in some principal cells and colocalized with H(+)-ATPase immunolabel. We conclude that both Rhbg and Rhcg are highly expressed in specific cells in the male reproductive tract where they can contribute to multiple components of male fertility.
    Reproduction 07/2013; 146(3):283-96. DOI:10.1530/REP-13-0154 · 3.17 Impact Factor
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