Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate.
OBJECTIVE
In polycystic liver diseases (PCLDs), increased cholangiocyte proliferation and fluid secretion are key features and cholangiocyte adenosine 3',5'-cyclic monophosphate (cAMP) is an important regulator of these processes. Thus, we assessed cAMP levels and evaluated octreotide (an analogue of somatostatin known to inhibit cAMP) in hepatic cyst growth using an in vitro model of cystogenesis and an in vivo animal model of autosomal recessive polycystic kidney disease (ARPKD), one of the PCLDs.


METHODS
Expression of somatostatin receptors (SSTRs) was assessed by reverse-transcription polymerase chain reaction and confocal microscopy in cholangiocytes from normal and polycystic kidney (PCK) rats, the ARPKD model of autosomal recessive polycystic kidney disease. Effects of octreotide on cAMP levels and cyst expansion were studied in vitro using PCK bile ducts grown in 3-dimensional culture. The effects of octreotide on hepatic and renal cystogenesis were investigated in PCK rats in vivo.


RESULTS
In cholangiocytes and serum of PCK rats, cAMP concentrations were approximately 2 times higher than in normal rats. SSTR subtypes that bind octreotide (ie, SSTR2, SSTR3, and SSTR5) were expressed in both normal and PCK cholangiocytes. In vitro, octreotide inhibited cAMP levels by 35% and reduced cyst growth by 44%. In vivo, octreotide lowered cAMP content in cholangiocytes and serum by 32%-39% and inhibited hepatic disease progression, leading to 22%-60% reductions in liver weight, cyst volume, hepatic fibrosis, and mitotic indices. Similar effects were observed in kidneys of PCK rats.


CONCLUSIONS
This preclinical study provides a strong rationale for assessing the potential value of octreotide in the treatment of PCLDs.
Masyuk
Tatyana V
TV
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Masyuk
Anatoliy I
AI
Torres
Vicente E
VE
Harris
Peter C
PC
Larusso
Nicholas F
NF
D000818:Animals; D001649:Bile Duct Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D003560:Cysts / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015282:Octreotide / Q000494:pharmacology* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D017044:Polycystic Kidney, Autosomal Recessive / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D005765:Gastrointestinal Agents; D017481:Receptors, Somatostatin; D000242:Cyclic AMP; D015282:Octreotide