Hepatic Cystogenesis Is Associated with Abnormal Expression and Location of Ion Transporters and Water Channels in an Animal Model of Autosomal Recessive Polycystic Kidney Disease

被引：59

作者：

Banales, Jesus M. ^{[1
,2
]}

Masyuk, Tatyana V. ^{[1
]}

Bogert, Pamela S. ^{[1
]}

Huang, Bing Q. ^{[1
]}

Gradilone, Sergio A. ^{[1
]}

Lee, Seung-Ok ^{[1
,3
]}

Stroope, Angela J. ^{[1
]}

Masyuk, Anatoliy I. ^{[1
]}

Medina, Juan F. ^{[2
]}

LaRusso, Nicholas F. ^{[1
]}

机构：

[1] Mayo Clin, Coll Med, Miles & Shirley Fiterman Ctr Digest Dis, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA

[2] Univ Navarra, Sch Med, Div Gene Therapy & Hepatol,Lab Mol Genet, Ctr Invest Med Ampl & Ciberehd,Clin Univ, E-31080 Pamplona, Spain

[3] Chonbuk Natl Univ, Sch Med, Jeonju, Jeonbuk, South Korea

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2008年 / 173卷 / 06期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.2353/ajpath.2008.080125

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

Polycystic kidney (PCK) rats are a spontaneous model of autosomal recessive polycystic kidney disease that exhibit cholangiocyte-derived liver cysts. We have previously reported that in normal cholangiocytes a subset of vesicles contain three proteins (ie, the water channel AQP1, the chloride channel CFTR, and the anion exchanger AE2) that account for ion-driven water transport. Thus, we hypothesized that altered expression and location of these functionally related proteins contribute to hepatic cystogenesis. We show here that under basal conditions and in response to secretin and hypotonicity, cysts from PCK rats expanded to a greater degree than cysts formed by normal bile ducts. Quantitative reverse transcriptase-polymerase chain reaction, immunoblot analysis, and confocal and immunoelectron microscopy aft indicated increased expression of these three proteins in PCK cholangiocytes versus normal cholangiocytes. AQP1, CFTR, and AE2 were localized preferentially to the apical membrane in normal rats while overexpressed at the basolateral. membrane in PCK rats. Exposure of the cholangiocyte basolateral membrane to CFTR inhibitors [5-nitro-2-(3-phenylpropylamino)benzoic acid and CFTRinh172], or Cl-/HCO3- exchange inhibitors (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate and 4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid disodium, salt hydrate) blocked secretin-stimulated fluid accumulation in PCK but not in normal cysts. Our data suggest that hepatic cystogenesis in autosomal recessive polycystic kidney disease may involve increased fluid accumulation because of overexpression and abnormal location of AQP1, CFTR, and AE2 in cystic cholangiocytes. Therapeutic interventions that block the activation of these proteins might inhibit cyst expansion in polycystic liver disease. (Am J Pathol 2008,173:1637-1646; DOI: 10.2353/ajpath.2008.080125)

引用

页码：1637 / 1646

页数：10

共 47 条

[1] VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice [J].