Renal Ammonia Metabolism and Transport

Abstract

Renal ammonia metabolism and transport mediates a central role in acid-base homeostasis. In contrast to most renal solutes, the majority of renal ammonia excretion derives from intrarenal production, not from glomerular filtration. Renal ammoniagenesis predominantly results from glutamine metabolism, which produces 2 NH4+ and 2 HCO3− for each glutamine metabolized. The proximal tubule is the primary site for ammoniagenesis, but there is evidence for ammoniagenesis by most renal epithelial cells. Ammonia produced in the kidney is either excreted into the urine or returned to the systemic circulation through the renal veins. Ammonia excreted in the urine promotes acid excretion; ammonia returned to the systemic circulation is metabolized in the liver in a HCO3−-consuming process, resulting in no net benefit to acid-base homeostasis. Highly regulated ammonia transport by renal epithelial cells determines the proportion of ammonia excreted in the urine versus returned to the systemic circulation. The traditional paradigm of ammonia transport involving passive NH3 diffusion, protonation in the lumen and NH4+ trapping due to an inability to cross plasma membranes is being replaced by the recognition of limited plasma membrane NH3 permeability in combination with the presence of specific NH3-transporting and NH4+-transporting proteins in specific renal epithelial cells. Ammonia production and transport are regulated by a variety of factors, including extracellular pH and K+, and by several hormones, such as mineralocorticoids, glucocorticoids and angiotensin II. This coordinated process of regulated ammonia production and transport is critical for the effective maintenance of acid-base homeostasis.

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

“…Ammonia is fundamentally different. Almost all urinary ammonia is produced in the kidney (47), and renal venous ammonia exceeds arterial ammonia, meaning that the kidneys actually increase systemic ammonia. Ammonia undergoes a complex set of transport events in the kidney, which determines the proportion of ammonia generated that is excreted in the urine as ammonia nitrogen versus that which enters the renal capillaries and is transported to the systemic circulation through the renal veins.…”

“…Changes in ammoniagenesis, such as during metabolic acidosis, are associated with changes in the expression of SNAT3, but not expression of apical Na 1 -dependent neutral amino acid transporter-1 (50). Ammoniagenesis primarily involves phosphate-dependent glutaminase, glutamate dehydrogenase, a-ketoglutarate dehydrogenase, and phosphoenolpyruvate carboxykinase (PEPCK) (47,51), and complete glutamine metabolism generates two NH 4 1 and two HCO 3 2 ions per glutamine. The bicarbonate produced is then transported across the basolateral membrane via electrogenic sodium-coupled bicarbonate co-transporter, isoform 1A (NBCe-1A), and serves as "new bicarbonate" generated by the kidney.…”

“…This enables changes in urinary ammonia to exceed, at least acutely, changes in ammoniagenesis (52). In most chronic acid-base disturbances, changes in ammoniagenesis account for the majority of the changes in urinary ammonia content (47). Importantly, renal epithelial cell ammonia transport determines the proportion of ammonia excreted in the urine.…”

Recent advances in understanding trans-epithelial acid-base regulation and excretion mechanisms in cephalopods

“…Moreover, co-localization of NHE3 and RhP strongly suggests an acid-trapping mechanism of NH 4 C similar to that demonstrated for diverse vertebrate excretory organs including skin, gill and kidneys. 107,114,115 For example in acid-secreting intercalated cells of the mammalian kidney acid-secretion is coupled to the export of ammonium ions that are trapped in the acidified urine. 106 Here, the basolateral localization of Rhbg and Rhcg is believed to facilitate the entry of the de-protonized ammonia (NH 3 ) from the blood into the cell where the majority of NH 3 is protonized to the ammonium ion at a physiological pH of approximately 7.2.…”

Evidence for ammonium conductance in a mouse thick ascending limb cell line

“…In essence, the kidneys excrete ${\text{NH}}_4^{+}$ to urine as they produce ${\text{HCO}}_3^{-}$, and the mechanism by which ${\text{NH}}_4^{+}$ excretion results in net acid excretion involves a series of sophisticated ${\text{NH}}_4^{+}$ transport processes in different parts of the nephron (Weiner and Verlander 2013; Hamm et al. 2015).…”