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2017 ; 74
(12
): 2283-2298
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Fluid shear stress-induced TGF-?/ALK5 signaling in renal epithelial cells is
modulated by MEK1/2
#MMPMID28168444
Kunnen SJ
; Leonhard WN
; Semeins C
; Hawinkels LJAC
; Poelma C
; Ten Dijke P
; Bakker A
; Hierck BP
; Peters DJM
Cell Mol Life Sci
2017[Jun]; 74
(12
): 2283-2298
PMID28168444
show ga
Renal tubular epithelial cells are exposed to mechanical forces due to fluid flow
shear stress within the lumen of the nephron. These cells respond by activation
of mechano-sensors located at the plasma membrane or the primary cilium, having
crucial roles in maintenance of cellular homeostasis and signaling. In this
paper, we applied fluid shear stress to study TGF-? signaling in renal epithelial
cells with and without expression of the Pkd1-gene, encoding a mechano-sensor
mutated in polycystic kidney disease. TGF-? signaling modulates cell
proliferation, differentiation, apoptosis, and fibrotic deposition, cellular
programs that are altered in renal cystic epithelia. SMAD2/3-mediated signaling
was activated by fluid flow, both in wild-type and Pkd1 (-/-) cells. This was
characterized by phosphorylation and nuclear accumulation of p-SMAD2/3, as well
as altered expression of downstream target genes and epithelial-to-mesenchymal
transition markers. This response was still present after cilia ablation. An
inhibitor of upstream type-I-receptors, ALK4/ALK5/ALK7, as well as
TGF-?-neutralizing antibodies effectively blocked SMAD2/3 activity. In contrast,
an activin-ligand trap was ineffective, indicating that increased autocrine TGF-?
signaling is involved. To study potential involvement of MAPK/ERK signaling,
cells were treated with a MEK1/2 inhibitor. Surprisingly, fluid flow-induced
expression of most SMAD2/3 targets was further enhanced upon MEK inhibition. We
conclude that fluid shear stress induces autocrine TGF-?/ALK5-induced target gene
expression in renal epithelial cells, which is partially restrained by
MEK1/2-mediated signaling.