Molecular Mechanisms of Renal Ammonia Transport

Weiner, I. David; Hamm, L. Lee

doi:10.1146/annurev.physiol.69.040705.142215

Cited by 137 publications

(115 citation statements)

References 128 publications

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“…1 excretion represents the other major mechanism whereby the kidneys excrete acid (66). Of the net acid excreted (or new HCO 3 2 generated) by the kidneys, approximately one-half to two-thirds (approximately 40-50 mmol/d) is because of NH 4 1 excretion in the urine.…”

Section: Nhmentioning

confidence: 99%

Acid-Base Homeostasis

Hamm¹,

Nakhoul²,

Hering-Smith³

2015

Clinical Journal of the American Society of Nephrology

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336

262

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Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO 3 2 and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO 3 2 is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.

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Section: Nhmentioning

confidence: 99%

Acid-Base Homeostasis

Hamm¹,

Nakhoul²,

Hering-Smith³

2015

Clinical Journal of the American Society of Nephrology

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336

262

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“…Although Rhag proteins appear to be mainly restricted to erythrocytes in mammals, Rhbg and Rhcg proteins are expressed in many tissues. The general pattern in most studies is that Rhbg proteins occur on basolateral membranes whereas Rhcg proteins are expressed on apical membranes, but exceptions are starting to emerge, especially with respect to Rhcg in the kidney (reviewed by Weiner and Hamm, 2007). Compared with mammals, fish have many more copies of Rh genes (Huang and Peng, 2005), and progress has been made in describing the tissue-specific expression and subcellular localization of some of the mRNA and proteins which they code, as outlined subsequently, but functional differentiation has not yet been teased out.…”

Section: Discovery Of Rh Glycoproteinsmentioning

confidence: 99%

“…Nevertheless, there is long-standing evidence, originating from the work of D.H. Evans and collaborators, that some sort of functional Na + /NH 4 + exchange mechanism exists in the gills of marine fish, involved in both ammonia excretion and acid-base regulation; the recent discovery of NHE-2 and NHE-3 isoforms in gill cell apical membranes of marine teleosts lends credence to this idea (reviewed by Evans, 2008). Interestingly, in this regard there is emerging evidence that NHE-3 may serve as a direct Na + /NH 4 + exchanger in the high NaCl environment of the proximal tubule of the mammalian kidney [summarized by Weiner and Hamm (Weiner and Hamm, 2007)]. Based on immunohistochemical localization only, Nakada et al (Nakada et al, 2007b) have proposed a dual pathway model involving basolateral Rhbg and apical Rhcg2 in pavement cells (somewhat similar to Fig.…”

Section: Future Directionsmentioning

confidence: 99%

A new paradigm for ammonia excretion in aquatic animals: role of Rhesus(Rh) glycoproteins

Wright

Wood

2009

Journal of Experimental Biology

339

256

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SummaryAmmonia excretion at the gills of fish has been studied for 80 years, but the mechanism(s) involved remain controversial. The relatively recent discovery of the ammonia-transporting function of the Rhesus (Rh) proteins, a family related to the Mep/Amt family of methyl ammonia and ammonia transporters in bacteria, yeast and plants, and the occurrence of these genes and glycosylated proteins in fish gills has opened a new paradigm. We provide background on the evolution and function of the Rh proteins, and review recent studies employing molecular physiology which demonstrate their important contribution to branchial ammonia efflux. Rhag occurs in red blood cells, whereas several isoforms of both Rhbg and Rhcg occur in many tissues. In the branchial epithelium, Rhcg appears to be localized in apical membranes and Rhbg in basolateral membranes. Their gene expression is upregulated during exposure to high environmental ammonia or internal ammonia infusion, and may be sensitive to synergistic stimulation by ammonia and cortisol. Rhcg in particular appears to be coupled to H + excretion and Na + uptake mechanisms. We propose a new model for ammonia excretion in freshwater fish and its variable linkage to Na + uptake and acid excretion. In this model, Rhag facilitates NH 3 flux out of the erythrocyte, Rhbg moves it across the basolateral membrane of the branchial ionocyte, and an apical "Na THE JOURNAL OF EXPERIMENTAL BIOLOGY 2304and helps to explain some of the discrepancies in the earlier literature. Retrospection on past controversiesSince the classic divided chamber experiments of Homer Smith (Smith, 1929), it has been known that freshwater fish excrete their nitrogen waste predominantly as ammonia through the gills. August Krogh (Krogh, 1939) presented circumstantial evidence that ammonia excretion is in some way linked to active Na + uptake at the gills of freshwater animals. Jean Maetz (Maetz and GarciaRomeu, 1964) presented experimental evidence for direct Na + /NH 4 + exchange linkage in freshwater fish. Since then, our understanding of how ammonia actually permeates the gills has become less and less clear, as various studies have led to conflicting conclusions. Evidence has been presented to reinforce the predominance of Na + /NH 4 + exchange (Maetz, 1973; Kerstetter and Keeler, 1976;Payan and Girard, 1978;Pressley et al., 1981;McDonald and Prior, 1988;McDonald and Milligan, 1988), whereas others have argued for the dominance of simple NH 3 diffusion down the partial pressure NH 3 gradient maintained by the CO 2 hydration reaction in the gill boundary layer (Cameron and Heisler, 1983;Wilson et al., 1994;Wilkie and Wood, 1994). Intermediate positions have included flexible coupling via diffusion trapping of NH 3 linked to Na + /H + or H + pump/Na + channel mechanisms (Avella and Bornancin, 1989;Heisler, 1990), or mixed mechanisms whereby ammonia moves partly by diffusion and partly by electroneutral exchange (Wright and Wood, 1985;Salama et al., 1999). The overall problem is that ammonia excretion h...

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“…Although a clear apical or basolateral gill orientation has not been determined for NHE1 (Edwards et al, 2005), both NHE2 and NHE3 have been localised to the apical region (Evans, 2008). NHEs are thought to play a role in acid-base regulation in both freshwater and seawater fish (Edwards et al, 2005), and in the proximal tubules of the mammalian kidney, NHE3 is thought to be involved in ammonia excretion with NH 4 + substituting for H + (Weiner and Hamm, 2006). Experimental evidence suggests that under low environmental ammonia conditions, little or no ammonia excretion occurs via apical Na + /NH 4 + exchange in seawater fish (Evans, 1982;Evans, 1984;Evans and More, 1988;Evans et al, 1979;Evans et al, 1989); however, under HEA conditions, apical NHE is thought to facilitate NH 4 + excretion in the mudskipper (Randall et al, 1999).…”

Section: Nhementioning

confidence: 99%

“…NKCC1 is thought to be involved in the basolateral uptake of NH 4 + in the kidney (Weiner and Hamm, 2006) as well as in colonic crypt cells together with Rh proteins (Worrell et al, 2008), and has also been implicated in ammonia-induced astrocyte swelling in the brain (Jayakumar et al, 2008). In seawater fish gills, NKCC1 is involved in salt secretion and has been detected in the basolateral regions of the MRCs in a number of species (Hwang and Lee, 2007).…”

Section: Nkcc1mentioning

confidence: 99%