Mechanism of Fluid Reabsorption in Kidney Proximal Tubule: Interplay Between Lateral Na ⁺ /K ⁺ ‐ <scp>ATPase</scp> and <scp>AQP1</scp> and <scp>SGLT1</scp> Mediated Water Fluxes

ABSTRACT Aims The mechanism of isosmotic water reabsorption in the kidney proximal tubule, with a focus on the interaction between the lateral Na + /K + ‐ATPase, apical water pathways mediated by AQP1 and SGLT1, and paracellular water flow through Claudin‐2. Methods A mathematical model of proximal tubular transport was used to compute coupled ion, solute, and water fluxes. The model included apical ENaC and a full electrogenic Na + /K + ‐ATPase formulation that incorporated its electromotive force, E pump , as a thermodynamic constraint linked to ATP hydrolysis at the pump site. Results Published cellular cation concentrations indicate metabolic stress in excised tubules, providing biophysical rationale for interpreting enhanced NHE3 activity and proton secretion in isolated proximal tubules as consequences of reduced ΔG ATP , while modeling apical Na + entry under non‐stressed conditions by ENaC. Active Na + transport generated a slightly hyperosmotic and hyperbaric lateral intercellular space, driving fluid efflux across the interspace basement membrane. Without ion recirculation, the absorbed fluid remained hyperosmotic. Isosmotic reabsorption therefore required ion recirculation between serosal fluid and the lateral intercellular space. SGLT1‐mediated glucose uptake redistributed water flow between AQP1, SGLT1 and the paracellular pathway, whereas total water reabsorption remained closely linked to active Na + transport, consistent with experiments. Conclusion Proximal tubular water reabsorption is not explained by passive osmotic equilibration alone, but emerges from thermodynamic coupling between active Na + transport, water permeability pathways, and regulated ion recirculation. The proximal tubule therefore functions as an ATP‐consuming epithelial fluid pump that maintains isosmotic reabsorption by using additional metabolic energy to convert initially hyperosmotic absorbate into isosmotic reabsorbed fluid.