Figure 8.

Two models of how the electroneutral Na/HCO₃ cotransporter NBCn2 could mediate the reabsorption of HCO₃⁻ and titration of non-CO₂/HCO₃⁻ buffers in the renal proximal tubule (PT). Guo et al. discovered that a variant of NBCn2 (first 4 N-terminal amino acids: MCDL) is present at the apical membrane of proximal-tubule (PT) cells [90]. Although NBCn2 is generally depicted as mediating NaHCO₃ uptake (A), evidence suggests that it in fact is an exchanger. If so, the simplest model is that it exchanges Na⁺ plus CO₃⁼ for HCO₃⁻ (B). (A) NBCn2 as a cotransporter. If the apical NBCn2 directly moves the filtered Na⁺ and HCO₃⁻ into the cytosol, the result would be a deficit of Na⁺ and HCO₃⁻ in the nanodomains near the transporter. One means of replenishing the lost NaHCO₃ would be the diffusion of Na⁺ and HCO₃⁻ from the bulk luminal fluid to the apical membrane. Another means of replenishing the HCO₃⁻ would be the conversion of CO₂ and H₂O to HCO₃⁻ and H⁺, facilitated by apical CA IV. Our simulations [90] suggest that the reaction (H₂O + CO₂ → H⁺ + HCO₃⁻) accounts for only a small fraction of total HCO₃⁻ replenishment. The newly produced HCO₃⁻ would move into the cytosol via NBCn2, whereas the newly produced H⁺ would either titrate B⁻ to form HB, or remain unbuffered. In the cytosol, most of the HCO₃⁻ arriving via NBCn2 would diffuse toward the basolateral membrane, for exit via the electrogenic Na/HCO₃ cotransporter NBCe1-A. However, a small fraction of the entering HCO₃⁻ would in principle, under the catalytic action of CA II, recycle back into the lumen—mostly via aquaporin 1 (AQP1)—as H₂O and CO₂. This diffusion of H₂O and CO₂ is in the direction opposite shown in Figure 7, but would ultimately be responsible for the titration of B⁻ to HB. In a real PT, the H₂O and CO₂ necessary to replenish luminal HCO₃⁻ could come from Na-H exchange and H⁺ pumping, as shown in Figure 7. (B) NBCn2 as an exchanger. In this model, filtered Na⁺ and HCO₃⁻ diffuses from the bulk luminal fluid towards NBCn2. The HCO₃⁻ that approaches NBCn2 dissociates into CO₃⁼ and H⁺, with CO₃⁼ entering the PT cytosol via NBCn2. Virtually all of the newly produced luminal H⁺ titrates the HCO₃⁻ that NBCn2 moves out of the PT cell. The result is the formation of luminal H₂O and CO₂—catalyzed by apical CA IV—and the subsequent influx of H₂O and CO₂, again mostly via AQP1, into the cytosol. Once inside the cell, the CO₂ and H₂O—catalyzed by CA II—would regenerate HCO₃⁻ for export into the lumen via NBCn2, and H⁺, which would titrate the incoming CO₃⁼ to HCO₃⁻, which would eventually exit the cell via NBCe1-A. Note that, in this scenario, virtually no luminal H⁺ would be left over to titrate B⁻ to HB. In other words, NBCn2 would appear to mediate the pure uptake of NaHCO₃ without titrating other buffers. AM, apical membrane; BLM, basolateral membrane; CA_Inh, carbonic anhydrase inhibitor.