We previously reported that
p38 mitogen-activated protein kinase (p38) and phosphorylated ERK are upregulated in
cyst epithelium of human renal dysplasia and obstructive uropathy in fetal lambs (Omori S, Fukuzawa R,
Hida M, Awazu M. Kidney Int 61: 899-906, 2002; Omori S, Kitagawa H, Koike J, Fujita H,
Hida M, Pringle KC, Awazu M. Kidney Int 73: 1031-1037, 2008). Dysplastic epithelium is characterized by proliferation, apoptosis, and upregulation of Pax2 and
transforming growth factor (TGF)-beta1. In the present study, we investigated whether cyclic mechanical stretching of ureteric bud cells, a mimic of the hydrodynamic derangement after fetal urinary tract obstruction, reproduces events seen in vivo. Cyclic stretch activated p38 and ERK and upregulated Pax2 expression in a time-dependent manner in ureteric bud cells. Stretch-stimulated Pax2 expression was suppressed by a p38 inhibitor,
SB203580, or a
MEK inhibitor,
PD98059. 5-Deoxyuridine incorporation was increased by stretch at 24 h, which was also abolished by
SB203580 or
PD98059. On the other hand, apoptosis was not induced at 24 h by stretch but was significantly increased at 48 h.
TGF-beta1 secretion was increased by stretch at 24 h, which was inhibited by
SB203580 or
PD98059. Inhibition of p38 or ERK as well as anti-
TGF-beta antibody abolished the stretch-induced apoptosis. Finally, exogenous
TGF-beta1 induced apoptosis of ureteric bud cells, which was inhibited by
SB203580 and
PD98059. In conclusion, cyclic stretch induces Pax2 upregulation, proliferation, and TGF-beta1-mediated apoptosis, features characteristic of dysplastic epithelium, via p38 and ERK in ureteric bud cells.