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

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Background: The secretin receptor (SCTR) is functionally expressed in the basolateral membrane of the β-intercalated cells (β-ICs) of the kidney cortical collecting duct, and stimulates urine alkalization by activating β-ICs. Interestingly, plasma secretin level increases during acute metabolic alkalosis, but its role in systemic acid-base homeostasis was unclear. We hypothesized that the secretin-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 (WT) and knockout (KO) mice. We also perfused isolated rat small intestines to study secretin release.

Results: In WT 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 intra-peritoneal 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. Additionally, our findings suggest that blood alkalinity increases secretin release from the small intestine, and that secretin action is critical for bicarbonate homeostasis.
TidsskriftJournal of the American Society of Nephrology : JASN
Sider (fra-til)1329-1342
Antal sider14
StatusUdgivet - 1 aug. 2023

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