Impaired renal base excretion in secretin receptor knock-out mice during prolonged base-loading
AimSecretin 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. MethodsUrine 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 hours of acid/base-loading by radioimmunoassay and qPCR, respectively. ResultsSCTR KO mice responded with diminished urine alkalization and a lesser reduction of urinary acid excretion when base-loaded for 48 hours. 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 HCO - associated with higher renal SCTR mRNA expression. ConclusionLoss 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. Key pointsO_LIIn mice, the receptor of the gut hormone secretin is required for the kidney to adequately handle a sustained base load. In mice with secretin receptor knockout, renal base excretion is impaired and metabolic alkalosis is aggravated and slower to resolve. C_LIO_LIBase-loaded knockout mice up-regulate pendrin protein abundance normally, the bicarbonate-secreting Cl-/HCO3-exchanger in collecting-duct {beta}-intercalated cells, but exhibit lower pendrin function. This suggests that the defect lies in the activation of pendrin, rather than in the regulation of its abundance. C_LIO_LIRenal secretin-receptor expression increases with higher arterial bicarbonate and plasma secretin, and renal secretin receptor expression, levels are lower in acid-loaded mice compared to base-loaded mice. This indicates that the secretin/secretin receptor system is itself affected by acid-base status/acid-base intake. C_LI