Balancing the acid-base books

Few quantities in the body are maintained as tightly as acidity: measured as the concentration of protons (H⁺) in our fluids. Blood pH normally stays between 7.35 and 7.45. A drift of a few tenths either way is enough to significantly stall enzymes, disturb heart rhythm and cloud consciousness. The body’s efforts to keep pH balance never let up because what we eat pushes against it every day.

Our dietary choices incur an acid-base debt [1, 2]. For example, a diet rich in eggs or cheese gives rise to significant levels of sulphuric and phosphoric acids, consuming the body’s store of bicarbonate (HCO₃⁻) [1]. Conversely, a diet predominantly of fruit and vegetables leaves organic anions that increase bicarbonate levels [1, 2]. While the average adult’s ‘Western’ diet has a net proton excess [1], there are mechanisms in place to help counter departures in either direction from the extracellular set point of pH 7.4 [3]. Here, we will observe one striking example of this kind of bi-directional adaptability in acid-base balance.

Let’s follow the prevalent scenario of acidic excess from diet. In the short term, any excess H⁺ is neutralized by plasma bicarbonate and exhaled as carbon dioxide, leaving a bicarbonate deficit in its wake [3]. Given that…

H⁺ + HCO₃⁻ ⇌ H₂O + CO₂

…the lungs cannot repay this deficit: hyperventilating blows off more CO₂, but every CO₂ exhaled takes a bicarbonate with it, such that the bicarbonate deficit remains untouched [3]. Instead, the kidneys have evolved two different strategies to help balance the bicarbonate books [3, 4].

The first process unfolds across the epithelial cells of the proximal tubule of the nephron [Wikipedia], where membrane proteins NHE3 (SLC9A3) and NBCe1 (SLC4A4) help reclaim bicarbonate that entered the urinary stream from glomerular ultrafiltration [5, 6]: there, protons secreted by apical NHE3 meet filtered bicarbonate in the lumen [3, 5]. The resultant CO₂ enters the epithelial cell, where it is split again in H⁺ and HCO₃⁻, with the latter carried by basolateral NBCe1 towards the blood [3, 5, 6]. This is a key example of asymmetric transport across an epithelial cell. In practice, the same cell has two distinct facets, one facing the outside and the other facing the inside of the body. Each facet has very distinctive machinery to closely control the directions of flow across the cell’s surfaces, and therefore decide precisely what leaves and what enters the body.

And now, the second process and a second example of asymmetric transport that happens downstream of the nephron in the collecting duct system [Wikipedia]. In our scenario of dietary acidic excess, the collecting ducts are now facing urinary fluid where most bicarbonate has already been mopped up by the nephron: urine enters the collecting duct system already acidic (pH of 6 to 6.5) and can leave it with even higher H⁺ concentrations (pH of 4.5 to 5.5) [3]. How can this intense acidification happen? This step also relies on the asymmetric deployment of membrane machinery across the two facets of the same cell. For instance, epithelial cells such as alpha Intercalated Cells (α-ICs) in the collecting duct system [Wikipedia] use a dedicated pump system, the apical V-ATPase, to force H⁺ against a mounting concentration gradient [7, 8]. Tight junctions between epithelial cells ensure that those protons do not easily seep back into the body [7]. Basolateral AE1 in α-ICs dumps towards the blood the HCO₃⁻ by-product from the internal production of H⁺ ions pumped out by the V-ATPase [7]. AE1’s returning of bicarbonate to the blood repays the deficit that the eggs-and-cheese diet ran up [4, 7].

It is interesting to note that the junction of the nephron to the collecting duct system, the Connecting Tubule (CNT) and Cortical Collecting Duct (CCD), show strong evidence of bi-directional adaptability to pH burdens [9]. For example, β-ICs sit along with α-ICs in the CCD [9, 10]. These β-ICs show the inverse configuration to α-ICs: their V-ATPase sits on the basolateral face and pumps H⁺ towards the blood, while an apical exchanger, pendrin, hands HCO₃⁻ into the urine in return for chloride [8, 9, 10]: in other words, conversely to α-ICs, β-ICs favour the asymmetric direction of protons into the body. Where the α-ICs repay a bicarbonate debt, the β-ICs spend any bicarbonate surplus [9].

Under omnivorous conditions, the α-ICs carry the day and the β-ICs mothball their pendrin in vesicles beneath the apical membrane [9]. But, if there is a radical change in diet (e.g., turning strictly vegan), the daily acid load falls away as fruit and vegetable anions cause an accumulation of excess bicarbonate [2]. Under such conditions, there is now more bicarbonate than the body wants, and the nephron must let some of it go [3, 9]. In response, pendrin moves to the apical surface of the β-IC and begins to secrete HCO₃⁻ into the urine [9]. Over days, more pendrin is synthesized by the β-IC [9]. Over weeks, the balance of the two populations in the CCT tilts in favour of β-ICs [10, 11, 12].

Transitioning from veganism to eggs and cheese means that the CNT and CCT epithelia retrace their steps: under sustained acid load, the best evidence says β-ICs remodel themselves into α-ICs, relocating the V-ATPase pump to the apical wall [10, 11, 12]. Given that the downstream medullary collecting ducts only carry α-ICs [9], the α/β adaptation to prevailing medium-term acid-base conditions appears to be unique to CNT and CCT segments [9, 10].

References

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