Tyrosine kinase dependent expression of TGF-beta induced by stretch in mesangial cells.
Increased glomerular hydraulic pressure has been suggested as a major causative factor in the development of glomerular sclerosis. The elevation of glomerular pressure increases the magnitude of stretch to mesangial cells. The study was, therefore, designed to investigate the effect of mechanical stretch on expression of TGF-beta and extracellular matrix components in cultured rat mesangial cells. The results showed that mechanical stretch stimulated mRNA expression for TGF-beta1 and TGF-beta3 in a time dependent manner, and that mesangial cells secreted substantial amounts of TGF-beta proteins in response to stretch. Stretch was also shown to stimulate mRNA expression for collagen types I and IV, and fibronectin, major components of mesangial extracellular matrix. The stretch-induced mRNA expression for extracellular matrix components was inhibited by neutralizing antibody to TGF-beta. Moreover, stretch-induced mRNA expression of TGF-beta was inhibited by tyrosine kinase inhibitors, genistein or herbimycin A, whereas Ca channel blockers nitrendipine or Gd3+, and inhibitors for protein kinase A or C had no effect. These findings indicate that stretch induced TGF-beta mRNA primarily through tyrosine kinase-dependent mechanisms in cultured rat mesangial cells, and the secreted TGF-beta may play a significant role for the stretch-induced expression of extracellular matrix proteins. Our results suggest that stretch-induced TGF-beta of mesangial cells might be a mediator in the progression of glomerular sclerosis as an autocrine/paracrine factor.
Hirakata
M
M
Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
Kaname
S
S
Chung
U G
UG
Joki
N
N
Hori
Y
Y
Noda
M
M
Takuwa
Y
Y
Okazaki
T
T
Fujita
T
T
Katoh
T
T
Kurokawa
K
K
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D017077:Culture Media, Conditioned; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000502:physiology*; D015432:Glomerulonephritis, Membranoproliferative / Q000209:etiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics* / Q000502:physiology
D002121:Calcium Channel Blockers; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D005353:Fibronectins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C