SLC4A5 encodes NBCe2, an electrogenic sodium bicarbonate cotransporter that mediates Na(+):HCO3(-) cotransport with a 1:2 or 1:3 stoichiometry 1. The protein is primarily expressed in renal tissue, including the collecting duct and proximal tubules, where it contributes to bicarbonate reabsorption and intracellular pH regulation 23. Under high-salt conditions, NBCe2 shows increased apical membrane expression in human renal proximal tubule cells, facilitating enhanced sodium and bicarbonate transport 43. Mechanistically, NBCe2 activity is stimulated by increases in intracellular sodium, with certain genetic variants showing hyperresponsive behavior through HNF4A-mediated mechanisms 4. Disease relevance includes hypertension susceptibility, as SLC4A5 variants are associated with increased blood pressure and salt sensitivity across multiple populations 256. Targeted mutation of Slc4a5 in mice causes persistent hypertension and metabolic acidosis, likely through impaired sodium-sparing bicarbonate reabsorption that triggers compensatory mechanisms involving increased sodium uptake 2. Additionally, SLC4A5 mutations have been linked to retinal pathology and identified as potential modifiers of neurological disease severity 78.