Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Am J Physiol Renal Physiol. 2012 Oct;303(7):F1089-98. doi: 10.1152/ajprenal.00242.2012. Epub 2012 Jul 18.
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 (PCK(di/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.
多囊肾病 (PKD) 和多囊肝病 (PLD) 会导致严重的发病率和死亡率。大量证据表明，环腺苷酸在其发病机制中起着重要作用。目前正在进行旨在降低靶组织中环腺苷酸水平的药物的临床试验。促胰液素可能有助于依赖腺苷酸环化酶的尿浓缩，并且是胆管细胞中腺苷酸环化酶的主要激动剂。为了研究促胰液素在 PKD 和 PLD 中的作用，我们研究了与常染色体隐性（PCK 大鼠）和显性（Pkd2(-/WS25) 小鼠）PKD 同源的啮齿动物模型中促胰液素和促胰液素受体的表达；外源性促胰液素给药对 PCK 大鼠、缺乏循环血管加压素的 PCK 大鼠 (PCK(di/di)) 和 Pkd2(-/WS25) 小鼠的影响；以及无功能促胰液素受体对 Pkd2(-/WS25):SCTR(-/-) 双突变体疾病发展的影响。两种模型的肾脏和肝脏促胰液素和促胰液素受体 mRNA 以及血浆促胰液素均增加，并且 Pkd2(-/WS25) 小鼠的肾脏和肝脏中促胰液素受体蛋白增加。然而，通过皮下渗透泵给予外源性促胰液素的作用最小或可以忽略不计，并且缺乏功能性促胰液素受体对 PKD 或 PLD 的严重程度没有影响。因此，促胰液素本身不太可能在 PKD 和/或 PLD 的发病机制中起重要作用。
