3E) In human control and ADPKD cholangiocytes, OCT inhibited the

3E). In human control and ADPKD cholangiocytes, OCT inhibited the rates of proliferation by 12.9% and 18.4%, respectively, and PAS by 21.9% and 33.7%, respectively (Fig. 3E). By BrdU assay, OCT and PAS suppressed, respectively, proliferation of: (1) rat control cholangiocytes by 15.5% and 24.4%; (2) PCK cholangiocytes by 25.1% and 32.9%; (3) human control

cholangiocytes by 12.5% and 19.8%; and (4) ADPKD cholangiocytes by 29.8% and 38.5% (Fig. 3F). Importantly, PAS repressed cell proliferation to a higher extent than OCT in rat and human control and cystic cholangiocytes (Fig. 3E,F). Under basal conditions, both control and PCK buy NVP-BEZ235 cysts expanded progressively over time (Fig. 4), although PCK structures grew to a greater extent. The circumferential area of control cysts enlarged by 92.07

± 5.45% compared to a 228.50 ± 25.32% increase in PCK cultures. In response to OCT, the expansion of control and PCK cysts was decreased 1.6 and 2.3-fold, respectively; whereas PAS reduced enlargement of control and PCK cysts by 2.2- and 4.7-fold, respectively. No differences were observed between OCT- or PAS-treated control cysts; however, the suppressive effects of PAS on growth of PCK cystic structures were more noteworthy compared to OCT (Fig. 4). Both somatostatin analogs were well tolerated by PCK rats and Pkd2WS25/- mice. In PCK rats, OCT and PAS reduced, respectively: (1) liver weights by 9% and 16%; (2) kidney weights by 7% and 14%; (3) hepatic cystic areas by 24% and 36%; (4) hepatic fibrotic areas by 10% and 19%; (5) renal cystic areas by 22% and 30%; and (6) renal fibrotic areas by 10% and 19% buy GSK1120212 (Supporting Table 1; Fig. 5). In Pkd2WS25/- mice, OCT and PAS treatment decreased, respectively: (1) liver weights by 17% and 22%; (2) kidney weights by 16% and 20%; (3) hepatic cystic areas by 22% and 34%; (4) hepatic fibrotic areas by 13% and 25%; (5) renal cystic areas by 19% and 30%; and (6) renal fibrotic areas by 18%

and 25% (Supporting Table 2; Fig. 6). Moreover, PAS decreased hepatic and renal cystic and fibrotic areas in PCK rats (Supporting Table 1; Fig. 5B,D) and Pkd2WS25/- mice (Supporting Table 2; Fig. 6B,D) to a greater extent than OCT. No changes in VEGF serum concentrations were observed in response to either OCT or PAS treatment in PCK rats. Serum levels of IGF1 were not affected by OCT, whereas PAS decreased it by 18% (P < 0.05) compared to control. selleck products Consistent with in vivo observation, suppressed secretion of IGF1 in the presence of PAS (but not OCT) was found in cultured rat control (by 10.8%; P < 0.03) and PCK (by 21.5%; P < 0.001) cholangiocytes, and human control (by 11.2%; P < 0.03) and ADPKD (by 15.7%; P < 0.01) cholangiocytes (Supporting Fig. 1). Expression of SSTR1, SSTR2, SSTR3, and SSTR5 (i.e., targets of OCT and/or PAS) were detected in cholangiocytes of control and PCK rats, control and Pkd2WS25/- mice, healthy human beings, and patients with PLD by confocal microscopy (Fig. 7A,B) and western blotting (Fig. 7C).

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