TY - JOUR
T1 - Insignificant effect of secretin in rodent models of polycystic kidney and liver disease
AU - Wang, Xiaofang
AU - Ye, Hong
AU - Ward, Christopher J.
AU - Chu, Jessica Y.S.
AU - Masyuk, Tatyana V.
AU - Larusso, Nicholas F.
AU - Harris, Peter C.
AU - Chow, Billy K.C.
AU - Torres, Vicente E.
PY - 2012
Y1 - 2012
N2 - Polycystic kidney (PKD) and liver (PLD) diseases cause significant morbidity and mortality. A large body of evidence indicates that cyclic AMP plays an important role in their pathogenesis. Clinical trials of drugs that reduce cyclic AMP levels in target tissues are now in progress. Secretin may contribute to adenylyl cyclase-dependent urinary concentration and is a major agonist of adenylyl cyclase in cholangiocytes. To investigate the role of secretin in PKD and PLD, we have studied the expression of secretin and the secretin receptor in rodent models orthologous to autosomal recessive (PCK rat) and dominant (Pkd2-/WS25 mouse) PKD; the effects of exogenous secretin administration to PCK rats, PCK rats lacking circulating vasopressin (PCKdi/di), and Pkd2 /WS25 mice; and the impact of a nonfunctional secretin receptor on disease development in Pkd2-/WS25:SCTR-/-double mutants. Renal and hepatic secretin and secretin receptor mRNA and plasma secretin were increased in both models, and secretin receptor protein was increased in the kidneys and liver of Pkd2-/WS25 mice. However, exogenous secretin administered subcutaneously via osmotic pumps had minimal or negligible effects and the absence of a functional secretin receptor had no influence on the severity of PKD or PLD. Therefore, it is unlikely that by itself secretin plays a significant role in the pathogenesis of PKD and/or PLD.
AB - Polycystic kidney (PKD) and liver (PLD) diseases cause significant morbidity and mortality. A large body of evidence indicates that cyclic AMP plays an important role in their pathogenesis. Clinical trials of drugs that reduce cyclic AMP levels in target tissues are now in progress. Secretin may contribute to adenylyl cyclase-dependent urinary concentration and is a major agonist of adenylyl cyclase in cholangiocytes. To investigate the role of secretin in PKD and PLD, we have studied the expression of secretin and the secretin receptor in rodent models orthologous to autosomal recessive (PCK rat) and dominant (Pkd2-/WS25 mouse) PKD; the effects of exogenous secretin administration to PCK rats, PCK rats lacking circulating vasopressin (PCKdi/di), and Pkd2 /WS25 mice; and the impact of a nonfunctional secretin receptor on disease development in Pkd2-/WS25:SCTR-/-double mutants. Renal and hepatic secretin and secretin receptor mRNA and plasma secretin were increased in both models, and secretin receptor protein was increased in the kidneys and liver of Pkd2-/WS25 mice. However, exogenous secretin administered subcutaneously via osmotic pumps had minimal or negligible effects and the absence of a functional secretin receptor had no influence on the severity of PKD or PLD. Therefore, it is unlikely that by itself secretin plays a significant role in the pathogenesis of PKD and/or PLD.
KW - Autosomal dominant polycystic kidney disease
KW - Cyclic AMP
KW - Polycystic kidney disease
KW - Secretin
KW - Secretin receptor
KW - Vasopressin
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U2 - 10.1152/ajprenal.00242.2012
DO - 10.1152/ajprenal.00242.2012
M3 - Article
C2 - 22811488
AN - SCOPUS:84867115802
VL - 303
SP - F1089-F1098
JO - American journal of physiology. Renal physiology
JF - American journal of physiology. Renal physiology
SN - 0363-6127
IS - 7
ER -