X-linked nephrogenic diabetes insipidus (NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. V2R inactivation prevents plasma membrane expression of the water channel AQP2 in the kidney collecting duct (CD) cells and impairs the kidney concentration ability. In the present work we showed that secretin receptor (SCTR) is functionally expressed at the basolateral membrane of the kidney collecting duct cells. Based on this observation, we infused the mouse model of X-NDI with SCT via osmotic pumps for 14 days at a dose of 2.5 mmol/Kg/day. Urinary parameters were not altered in SCT-infused animals. Interestingly, however, SCT significantly increased AQP2 levels in the CD, although the protein was mostly accumulated in the intracellular storage vesicles and hardly detectable at the plasma membrane. As we previously reported that fluvastatin (Flu) treatment increases AQP2 plasma membrane expression in the CD cells of wt mice, SCT-infused X-NDI mice received a single injection of Flu (50 mg/Kg). Interestingly, during the following 6 hours of observation, the diuresis of mice treated with SCT+Flu was reduced by nearly 90% and urine osmolality doubled. Analysis of the kidneys confirmed that SCT increased intracellular stores of AQP2 and the addition of Flu promoted AQP2 accumulation at the plasma membrane. Taken together these evidence indicate that the association of SCT and Flu might represent a novel and effective pharmacological treatment for X-NDI.
A novel treatment for X-linked nephrogenic diabetes insipidus: the secret in secretin?
PROCINO, Giuseppe;Milano S;SVELTO, Maria
2013-01-01
Abstract
X-linked nephrogenic diabetes insipidus (NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. V2R inactivation prevents plasma membrane expression of the water channel AQP2 in the kidney collecting duct (CD) cells and impairs the kidney concentration ability. In the present work we showed that secretin receptor (SCTR) is functionally expressed at the basolateral membrane of the kidney collecting duct cells. Based on this observation, we infused the mouse model of X-NDI with SCT via osmotic pumps for 14 days at a dose of 2.5 mmol/Kg/day. Urinary parameters were not altered in SCT-infused animals. Interestingly, however, SCT significantly increased AQP2 levels in the CD, although the protein was mostly accumulated in the intracellular storage vesicles and hardly detectable at the plasma membrane. As we previously reported that fluvastatin (Flu) treatment increases AQP2 plasma membrane expression in the CD cells of wt mice, SCT-infused X-NDI mice received a single injection of Flu (50 mg/Kg). Interestingly, during the following 6 hours of observation, the diuresis of mice treated with SCT+Flu was reduced by nearly 90% and urine osmolality doubled. Analysis of the kidneys confirmed that SCT increased intracellular stores of AQP2 and the addition of Flu promoted AQP2 accumulation at the plasma membrane. Taken together these evidence indicate that the association of SCT and Flu might represent a novel and effective pharmacological treatment for X-NDI.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
