Role of NH3 and NH4+ transporters in renal acid-base transport

RhBG/Rhbg.

RhBG/Rhbg is expressed in a wide variety of organs involved in ammonia metabolism, including kidneys, liver, skin, lung, stomach, and gastrointestinal tract (42, 44, 68, 87, 98, 107). In kidneys, the DCT, CNT, ICT, CCD, OMCD, and the IMCD express basolateral Rhbg (87, 98). In general, both intercalated and principal cells express Rhbg, and intercalated cell Rhbg expression exceeds principal cell expression. The exceptions are the CCD B-type intercalated cell, which does not express Rhbg detectable with immunohistochemistry, and the IMCD, where only intercalated cells express Rhbg (98). Rhbg’s basolateral expression appears due to basolateral stabilization through specific interactions of its cytoplasmic carboxy-terminus with ankyrin-G (69). The human kidney expresses high amounts of RhBG mRNA (68), but a recent study using a variety of antibodies did not detect RhBG protein expression (17).

RhBG/Rhbg transports both ammonia and the ammonia analog methylammonia. Most studies show that Rhbg mediates electroneutral, Na+- and K+-independent, NH3 transport (71, 73, 119), while another identified electrogenic NH4+ transport (84). The explanation for this discrepancy is not known. In all of these studies, the affinity for ammonia was ∼2-4 mM. Importantly, both electroneutral NH3 transport and electrogenic NH4+ transport facilitate basolateral ammonia uptake.

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Rhbg’s specific role in renal ammonia metabolism is controversial at present. Several studies suggest it can contribute to ammonia secretion in specific conditions. In the mouse, metabolic acidosis increased renal ammonia excretion and induced a progressive, time-dependent increase in Rhbg protein in the CNT, ICT, CCD, OMCD, and the IMCD in one study (12). In another study, which examined only the OMCD, metabolic acidosis increased Rhbg mRNA expression (protein expression was not examined) (22). These studies contrast with findings in the rat, where metabolic acidosis did not detectably alter Rhbg expression (90). In mice, genetic deletion of pendrin, an apical Cl−/HCO3− exchanger present in type B and non-A, non-B intercalated cells, decreased Rhbg expression (55). Since pendrin deletion increased urine acidification, which otherwise would increase ammonia excretion, decreased Rhbg expression may have normalized ammonia excretion rates. Finally, Rhcg deletion, either from the entire collecting duct or only from intercalated cells, increased Rhbg expression in acid-loaded mice, suggesting increased Rhbg protein expression contributed to ammonia excretion in the absence of Rhcg (61, 62). The consistent observation in the mouse that changes in Rhbg expression either parallel changes in ammonia excretion or compensate for genetic deletion of other proteins involved in renal acid-base homeostasis suggest Rhbg contributes to renal ammonia excretion.

However, studies examining genetic Rhbg deletion have reached differing conclusions as to Rhbg’s physiological role. In one study, mice with global Rhbg deletion were examined. These mice had normal basal acid-base parameters and basal ammonia excretion, normal increases in urinary ammonia excretion in response to acid loading, and normal basolateral NH3 and NH4+ permeability in microperfused CCD segments (19). These findings suggested Rhbg did not contribute to renal ammonia metabolism. Our laboratory examined mice with intercalated cell-specific Rhbg deletion (12). Basal ammonia excretion was not altered, but there was a substantial adaptive change in proximal tubule glutamine synthetase expression, which may have enabled normal rates of unstimulated ammonia excretion. With acid loading, intercalated cell-specific Rhbg deletion significantly impaired the expected increase in urinary ammonia excretion. These findings suggested Rhbg expression contributes to renal ammonia excretion and that adaptive responses to Rhbg deletion may mask Rhbg’s role under specific circumstances.

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