Hepatocyte growth factor induces branching tubulogenesis in MDCK cells by modulating the activin-follistatin system.
BACKGROUND
The activin-follistatin system is expressed in tubular cells of the kidney. The present study was conducted to examine the role of the activin-follistatin system in tubulogenesis using Madin-Darby canine kidney (MDCK) cells as a model system.


METHODS
Tubulogenesis was assessed using MDCK cells cultured in collagen gel. The effect of recombinant human activin A on tubulogenesis was examined. Blockade of the action of endogenous activin was achieved by either adding follistatin or transfection of dominant-negative mutant of the type II activin receptor. The production of activin A was examined by Northern blotting, in situ hybridization, and Western blotting.


RESULTS
MDCK cells expressed mRNA for the betaA subunit of activin. These cells formed spherical cysts when cultured in collagen gel. Hepatocyte growth factor (HGF) added to the spherical cysts induced branching tubulogenesis. When activin A was added together with HGF, activin A blocked the branching tubulogenesis induced by HGF, and the activin-treated cells were scattered. Conversely, follistatin, an antagonist of activin A, induced branching tubulogenesis qualitatively similar to that induced by HGF. Adenovirus vector-mediated transfer of the gene encoding truncated type II activin receptor, which acts as a dominant negative mutant, also induced branching tubulogenesis. Finally, HGF markedly inhibited the production of activin A in MDCK cells cultured in collagen gel.


CONCLUSIONS
Activin A produced in MDCK cells tonically inhibits branching tubulogenesis, and HGF induced branching tubulogenesis mainly by blocking the production of activin A.
Maeshima
A
A
Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, and Third Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Zhang
Y Q
YQ
Furukawa
M
M
Naruse
T
T
Kojima
I
I
D028341:Activins; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D038681:Follistatin; D005782:Gels; D015870:Gene Expression / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007265:Inhibins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007684:Kidney Tubules / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D007763:Lac Operon; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D038681:Follistatin; D005782:Gels; D006023:Glycoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins; D017228:Hepatocyte Growth Factor; D003094:Collagen