A putative role of secretin to regulate water homeostasis

Abstract

Secretin was first discovered as a gastrointestinal hormone a century ago, and to date, the role of secretin in regulating functions of exocrine pancreas is firmly established. The notion of secretin as a neuropeptide has recently received a revived attention, our group proposed that secretin functions as a retrograde messenger in the cerebellum to facilitate GABA release from the basket cells. In this report, the role of secretin in the hypothalamo – pituitary axis was investigated. We demonstrated that, upon potassium-evoked depolarization, secretin could be released in the hypothalamus and pituitary. In addition, secretin and its receptor were found to co-express with vasopressin in SON and PVN of the hypothalamus as well as the posterior pituitary. In the SON, intracerebroventricular administration of secretin was able to activate vasopressin gene expression via the cAMP/c-fos pathway. To examine further the physiologic functions of secretin, secretin receptor gene knockout mice (deletion of exon 10) were produced and phenotypic analyses revealed that secretin receptor knockout mice (SCTR / ) consistently had full and distended urinary bladders. These mutants drank and urinated more, while the osmolality, as well as the concentrations of Na+ , K+ , Cl , urea and creatinine, were lowered than those of the wild-types. Intraperitoneal injection of dDAVP suggested a normal urine-concentrating ability by vasopressin in SCTR / . The phenotypes observed were likely due to a reduced expression of the water channel aquaporin-3 in kidney as shown in real-time PCR and Western blot analyses. Based on these findings, we propose a role of secretin in modulating water homeostasis at multiple levels including the hypothalamus, posterior pituitary and kidney.