p38 MAP-kinase regulates function of gap and tight junctions during regeneration of rat hepatocytes.
OBJECTIVE
Hepatocyte regeneration is considered to be associated with adaptive changes in expression of gap and tight junctions through multiple signal transduction pathways including p38 MAP-kinase. The role of the stress responsitive MAP-kinase, p38 MAP-kinase, signaling pathway in function of gap and tight junctions was examined during regeneration of rat hepatocytes in vivo and in vitro.


METHODS
We examined changes in formation, expression and function of gap and tight junctions in rat livers after 70% partial hepatectomy and in primary cultures of rat hepatocytes, by using a p38 MAP-kinase inhibitor, SB203580.


RESULTS
When p38 MAP-kinase was activated during partial hepatectomy, down-regulation of Cx32 and up-regulation of claudin-1 were observed. By SB203580 treatment, the down-regulation of Cx32 was inhibited and the up-regulation of claudin-1 was enhanced, well maintaining the structures of gap and tight junctions. SB203580 treatment did not affect the increase of hepatocyte proliferation. In EGF induced proliferative rat hepatocytes treated with SB203580, the expression and function of Cx32 and claudin-1 were increased.


CONCLUSIONS
Dynamic changes of formation of gap and tight junctions during regeneration of rat hepatocytes in vivo and in vitro are in part controlled via a p38 MAP-kinase signaling pathway, and are independent of cell growth.
Yamamoto
Toshinobu
T
Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo 060-8556, Japan.
Kojima
Takashi
T
Murata
Masaki
M
Takano
Ken-Ichi
K
Go
Mitsuru
M
Hatakeyama
Naoko
N
Chiba
Hideki
H
Sawada
Norimasa
N
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D062445:Claudin-1; D062465:Claudin-3; D057167:Claudins; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D017629:Gap Junctions / Q000201:enzymology*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D019108:Tight Junctions / Q000201:enzymology*; D062826:Zonula Occludens-1 Protein; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097002:Gap Junction beta-1 Protein
D015820:Cadherins; D062445:Claudin-1; D062465:Claudin-3; D057167:Claudins; D017630:Connexins; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D007093:Imidazoles; D008565:Membrane Proteins; D062793:Occludin; D010750:Phosphoproteins; D011725:Pyridines; D012333:RNA, Messenger; D062826:Zonula Occludens-1 Protein; D048051:p38 Mitogen-Activated Protein Kinases; D000097002:Gap Junction beta-1 Protein; C568114:Cldn1 protein, rat; C491874:Cldn2 protein, rat; C568124:Cldn3 protein, rat; C568987:Ocln protein, rat; C569044:Tjp1 protein, rat; C093642:SB 203580