Ga. Tanner et al., AN IN-VITRO TEST OF THE CELL STRETCH-PROLIFERATION HYPOTHESIS OF RENAL CYST ENLARGEMENT, Journal of the American Society of Nephrology, 6(4), 1995, pp. 1230-1241
In renal cystic disease, fluid accumulation within cyst lumens might s
tretch cyst walls and in this way stimulate cell proliferation. To tes
t this idea, the effects of mechanical stretch on Madin-Darby canine k
idney cells grown as cysts in a hydrated collagen gel or as monolayers
on collagen-coated Flexcell membranes were examined. The percentage o
f cells synthesizing DNA (labeling index) was determined by measuring
bromodeoxyuridine incorporation and counting cell numbers. The distens
ion of single cysts for 1 h by the intraluminal injection of saline fa
iled to produce a significant increase in labeling index. The exposure
of cysts for 2.5 h to 1 mM dibutyryl cAMP + 0.1 mM isobutylmethylxant
hine led to a 37% increase in luminal surface area (due to stimulated
fluid secretion) and a 30% increase in labeling index. The stretch (25
%) of Madin-Darby canine kidney monolayers approximately doubled the l
abeling index between 12 and 24 h after starting the stretch. After 48
h, the cell population density was significantly increased (P < 0.001
), from 41.9 +/- 0.2 (SE; N = 12) to 48.2 +/- 0.5 (N = 12) cells/10,00
0 mu m(2). The labeling index increased linearly with applied stretch,
from 7.2 +/- 0.3% (N = 36) with no stretch to 16.2 +/- 1.0% (N = 6) w
ith 30% stretch. Stretch had to be maintained for 8 h or more to produ
ce an increase in labeling index at 18 h. No evidence was obtained for
the release of a diffusible growth factor by stretched monolayers. Th
e increase in labeling index induced by stretch was unaffected by 50 m
u M gadolinium, a stretch-activated channel blocker, but was abolished
by 5 mu g/mL cytochalasin B, an actin microfilament-disrupting agent.
It was concluded that prolonged stretch stimulates renal epithelial c
ells to synthesize DNA. This supports the idea that increased wall ten
sion in renal cysts may stimulate cell proliferation and, thereby, may
contribute to cyst enlargement.