["Acta Physiologica, Volume 242, Issue 9, September 2026. ", "\nABSTRACT\n\nAim\nSecretin was recently found to play a pivotal role in the renal adaptation to acute base excess. Here, secretin increases pendrin‐dependent HCO3− secretion from the beta‐intercalated cells in the cortical collecting ducts. Whether secretin and its receptor play a role during prolonged base‐loading remains unknown.\n\n\nMethods\nUrine and blood acid–base analyses were carried out in secretin receptor (SCTR) KO and WT mice at baseline and after 1 and up to 8 days of base‐loading with NaHCO3‐enriched drinking water. Changes in pendrin protein abundance and function were assessed by immunoblotting and isolated tubule perfusion experiments. Plasma secretin levels and renal SCTR expression were assessed after 24 h of acid/base‐loading by radioimmunoassay and qPCR, respectively.\n\n\nResults\nSCTR KO mice responded with diminished urine alkalization and a lesser reduction of urinary acid excretion when base‐loaded for 48 h. Concordantly, SCTR KO mice presented with increased blood base retention compared with WTs. Base‐loaded SCTR WT and KO mice showed comparable total pendrin protein abundance. Despite this, pendrin function was markedly lower in SCTR KO mice. Base‐loaded mice had higher plasma secretin and renal SCTR levels compared with acid‐loaded mice. Higher arterial HCO3− associated with higher renal SCTR mRNA expression.\n\n\nConclusion\nLoss of the SCTR diminishes renal base excretion capacity and exacerbates systemic base accumulation during prolonged base‐loading. Further, plasma secretin and renal SCTR mRNA levels are modulated by acid–base intake. These findings further support a central role of secretin and its receptor in the regulation of both acute and prolonged base excess.\n\n"]