Angiotensin II stimulates DNA synthesis of rat pancreatic stellate cells by activating ERK through EGF receptor transactivation.
Although angiotensin II (Ang II) is known to participate in pancreatic fibrosis, little is known as to the mechanism by which Ang II promotes pancreatic fibrosis. To elucidate the mechanism, we examined the action of Ang II on the proliferation of rat pancreatic stellate cells (PSCs) that play central roles in pancreatic fibrosis. Immunocytochemistry and Western blotting demonstrated that both Ang II type 1 and type 2 receptors were expressed in PSCs. [3H]Thymidine incorporation assay revealed that Ang II enhanced DNA synthesis in PSCs, which was blocked by Ang II type 1 receptor antagonist losartan. Western blotting using anti-phospho-epidermal growth factor (EGF) receptor and anti-phospho-extracellular signal regulated kinase (ERK) antibodies showed that Ang II-activated EGF receptor and ERK. Both EGF receptor kinase inhibitor AG1478 and MEK1 inhibitor PD98059 attenuated ERK activation and DNA synthesis enhanced by Ang II. These results indicate that Ang II stimulates PSC proliferation through EGF receptor transactivation-ERK activation pathway.
Hama
Kouji
K
Department of Gastroenterology, Jichi Medical School, Tochigi 329-0498, Japan.
Ohnishi
Hirohide
H
Yasuda
Hiroshi
H
Ueda
Namiki
N
Mashima
Hirosato
H
Satoh
Yukihiro
Y
Hanatsuka
Kazunobu
K
Kita
Hiroto
H
Ohashi
Akira
A
Tamada
Kiichi
K
Sugano
Kentaro
K
D000804:Angiotensin II / Q000235:genetics / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis; D011945:Receptors, Angiotensin / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014316:Tritium
D057911:Angiotensin Receptor Antagonists; D004791:Enzyme Inhibitors; D005419:Flavonoids; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D011994:Recombinant Proteins; D014316:Tritium; D000804:Angiotensin II; D004247:DNA; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D019808:Losartan; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D013936:Thymidine