Cyclic stretching force selectively up-regulates transforming growth factor-beta isoforms in cultured rat mesangial cells.
Glomerular distention from increased intraglomerular pressure stretches mesangial cells (MCs). Stretching MCs in culture stimulates extracellular matrix accumulation, suggesting that this may be a mechanism for glomerular hypertension-associated glomerulosclerosis. We examined whether mechanical stretching serves as a stimulus for the synthesis and activation of the prosclerotic molecule transforming growth factor (TGF)-beta, thus providing a potential system for auto-induction of extracellular matrix. Rat MCs cultured on flexible-bottom plates were subjected to cyclic stretching for up to 3 days and then assayed for TGF-beta mRNA, secretion of TGF-beta, and localization of active TGF-beta by immunostaining. MCs contained mRNA for all three mammalian isoforms of TGF-beta. Cyclic stretching for 36 hours increased TGF-beta1 and TGF-beta3 mRNA levels approximately twofold, without altering the levels of TGF-beta2 mRNA. This was followed at 48 to 72 hours by the increased secretion of both latent and active TGF-beta1. Latent, but not active, TGF-beta3 secretion also increased whereas the levels of TGF-beta2 were unaffected by mechanical force. The stretching force in this system is unequally distributed over the culture membrane. Localization of active TGF-beta by immunostaining demonstrated that the quantity of cell-associated cytokine across the culture was directly proportional to the zonal amplitude of the stretching force. These results demonstrate that stretching force stimulates MCs to selectively release and activate TGF-beta1. This mechanical induction of TGF-beta1 may help explain the increased extracellular matrix associated with intraglomerular hypertension.
Riser
B L
BL
Department of Internal Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital, MI 48202, USA.
Cortes
P
P
Heilig
C
C
Grondin
J
J
Ladson-Wofford
S
S
Patterson
D
D
Narins
R G
RG
D000818:Animals; D018929:Cell Culture Techniques; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism*; D007150:Immunohistochemistry; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta