Loss of the Secretin Receptor Impairs Renal Bicarbonate Excretion and Aggravates Metabolic Alkalosis in Mice during Acute Base-Loading

Abstract

Background The secretin receptor (SCTR) is functionally expressed in the basolateral membrane of the β-intercalated cells of the kidney cortical collecting duct and stimulates urine alkalization by activating the β-intercalated cells. Interestingly, the plasma secretin level increases during acute metabolic alkalosis, but its role in systemic acid–base homeostasis was unclear. We hypothesized that the SCTR system is essential for renal base excretion during acute metabolic alkalosis. Methods We conducted bladder catheterization experiments, metabolic cage studies, blood gas analysis, barometric respirometry, perfusion of isolated cortical collecting ducts, immunoblotting, and immunohistochemistry in SCTR wild-type and knockout (KO) mice. We also perfused isolated rat small intestines to study secretin release. Results In wild-type mice, secretin acutely increased urine pH and pendrin function in isolated perfused cortical collecting ducts. These effects were absent in KO mice, which also did not sufficiently increase renal base excretion during acute base loading. In line with these findings, KO mice developed prolonged metabolic alkalosis when exposed to acute oral or intraperitoneal base loading. Furthermore, KO mice exhibited transient but marked hypoventilation after acute base loading. In rats, increased blood alkalinity of the perfused upper small intestine increased venous secretin release. Conclusions Our results suggest that loss of SCTR impairs the appropriate increase of renal base excretion during acute base loading and that SCTR is necessary for acute correction of metabolic alkalosis. In addition, our findings suggest that blood alkalinity increases secretin release from the small intestine and that secretin action is critical for bicarbonate homeostasis.

Novel functions of the anion exchanger AE4 (SLC4A9)

“…Several receptors have been found to influence the activity of ICs. For example, the proton-activated G protein-coupled receptor GPR4 impacts on α-ICs activity [ 63 ], the insulin receptor-related receptor (IRR) affects β-ICs activity [ 18 ], and the hormone secretin stimulates HCO 3 - secretion of β-ICs via its receptor SCTR [ 5 ]. As metabolic acidosis and alkalosis are characterized by a change in plasma HCO 3 - concentration [ 4 ], a direct influence of a derailed extracellular electrolyte composition on the activity of β-ICs is likely [ 12 ].…”

“…Together with NKCC1 (SLC12A2), AE4 contributes to the high intracellular Cl - concentration that enables apical Cl - secretion via a Ca 2+ -dependent Cl - channel (CaCC). E Basolateral (interstitium/blood) and apical (urine) transporters and receptors of β-ICs shown to be directly or indirectly involved in HCO 3 - secretion (pendrin (SLC26A4), AE4 (SLC4A9) [ 73 ], SCTR secretin receptor [ 5 ] , ClC-K2 chloride channel [ 61 ] [ 25 ], KCC3a K + /Cl - cotransporter [ 20 ], CFTR cystic fibrosis transmembrane conductance regulator [ 9 ]) …”

“…Similarly, patients with Pendred syndrome, a disease caused by a mutation in the pendrin gene ( Slc26a4/Pds ), show hypochloremic metabolic alkalosis when exposed to an increased alkali load or a thiazide treatment [ 80 ]. Recent studies have shown that loss of the Cl - channel CFTR [ 69 , 8 , 7 ] or the secretin receptor (SCTR) [ 5 ] also impairs renal HCO 3 - secretion and causes metabolic alkalosis upon perturbation.…”

“…According to recent findings, cAMP is an important intracellular signaling molecule in β-ICs [ 10 ]. The hormone secretin enhances the activity of pendrin and urinary HCO 3 - secretion [ 9 , 5 ] through binding to its G protein-coupled receptor in the basolateral membrane of β-ICs (SCTR, Fig. 2 E) [ 6 ].…”