Gastrointestinal secretions are rich in chloride, with gastric secretions the predominant source. In the stomach, chloride secreted by apical chloride channels in parietal cells will match hydrogen ions released by the H+
-ATPase antiporter pumps (proton pumps), forming hydrochloric acid. Basal output of this acid is in the range 0 to 11 mmol/hour, increasing to 10 to 63 mmol/hour with meals [43
]. This load of acid, and thus chloride, is regulated by synergistic activities of histamine, gastrin and acetylcholine.
Chloride is also the main electrolyte driving fluid secretion throughout the intestinal epithelium. Paracellular movement of sodium that accompanies transepithelial chloride secretion results in luminal sodium chloride, which forms the osmotic pressure for water movement with secretions of 8 l/day [44
], which are largely reabsorbed throughout the intestinal tract.
Chloride is primarily excreted by the kidney. An average of 19,440 mmol is filtered through the kidneys every day, with 99.1% being reabsorbed, leaving only 180 mmol excreted per day [45
]. Most of the reabsorption occurs in the proximal tubule, by passive reabsorption, ion conductance or active coupled transport with other ions [46
]. Chloride reabsorption involves members of the solute carrier (SLC) gene families SLC26 and SLC24. These two gene families are expressed in various parts of the kidney, particularly in key components of renal acid-base regulation; that is, renal proximal tubules and intercalated cells of distal nephron. The intercalated cells are further differentiated into type A (alpha) cells that excrete protons and type B (beta) cells that secrete bicarbonate and reabsorb chloride [47
]. The transport activities of the two SLC families underline the role of chloride in renal acid-base regulation.
The SLC26 family are primarily chloride-anion exchangers; exchanging sulphate, iodide, formate, oxalate, hydroxyl ion and bicarbonate anions [47
]. They include SLC26A6 in the proximal tubule that mediates apical chloride-anion exchange, and SLC26A4 (pendrin) in the distal nephron that mediates chloride-anion exchange across the luminal membrane of type B intercalated cells.
The SLC4 solute carriers, on the other hand, predominantly function as chloride-bicarbonate and anion exchangers and sodium-bicarbonate co-transporters (NBC). Examples are SLC4A1 (also known as AE1), which mediates chloride-bicarbonate exchange in the basolateral membrane of type A intercalated cells (exchange of chloride into intercalated cells and bicarbonate into plasma), and SLC4A4 (also known as NBC1), which mediates sodium-bicarbonate co-transport in renal proximal tubule cells [46
These renal chloride carriers are key components of suggested models for physicochemical renal acid-base regulation [46
]. Figure shows an example of such regulation across proximal tubule cells. Physicochemical modelling of distal renal tubular acidosis from mutation of SLC4A1 (AE1) and proximal renal tubular acidosis from mutation of SLC4A4 (NBC1) [49
] has also consolidated the argument for the Stewart approach. This renal tubular acidosis modelling focuses on renal net handling of Na+
, the SID constituents, which means that chloride movement is no longer secondary to bicarbonate changes. In another physicochemical viewpoint, a departure from the conventional explanation of ammonium ion NH4+
as a carrier of H+
has been proposed [50
should instead be seen as a weak cation that, by co-excretion with chloride, allows loss of chloride without sodium or potassium.
Figure 2 Integration of proximal convoluted tubule chloride transport mechanisms with strong ion difference and partial pressure. Chloride is reabsorbed from passive paracellular transport, conductance and active coupled transport at both apical and basolateral (more ...)