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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Physiol+Renal+Physiol
2014 ; 307
(2
): F159-71
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RhoA/Rho kinase mediates TGF-?1-induced kidney myofibroblast activation through
Poldip2/Nox4-derived reactive oxygen species
#MMPMID24872317
Manickam N
; Patel M
; Griendling KK
; Gorin Y
; Barnes JL
Am J Physiol Renal Physiol
2014[Jul]; 307
(2
): F159-71
PMID24872317
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The small G proteins Rac1 and RhoA regulate actin cytoskeleton, cell shape,
adhesion, migration, and proliferation. Recent studies in our laboratory have
shown that NADPH oxidase Nox4-derived ROS are involved in transforming growth
factor (TGF)-?1-induced rat kidney myofibroblast differentiation assessed by the
acquisition of an ?-smooth muscle actin (?-SMA) phenotype and expression of an
alternatively spliced fibronectin variant (Fn-EIIIA). Rac1 and RhoA are essential
in signaling by some Nox homologs, but their role as effectors of Nox4 in kidney
myofibroblast differentiation is not known. In the present study, we explored a
link among Rac1 and RhoA and Nox4-dependent ROS generation in TGF-?1-induced
kidney myofibroblast activation. TGF-?1 stimulated an increase in Nox4 protein
expression, NADPH oxidase activity, and abundant ?-SMA and Fn-EIIIA expression.
RhoA but not Rac1 was involved in TGF-?1 induction of Nox4 signaling of kidney
myofibroblast activation. TGF-?1 stimulated active RhoA-GTP and increased Rho
kinase (ROCK). Inhibition of RhoA with small interfering RNA and ROCK using
Y-27632 significantly reduced TGF-?1-induced stimulation of Nox4 protein, NADPH
oxidase activity, and ?-SMA and Fn-EIIIA expression. Treatment with
diphenyleneiodonium, an inhibitor of NADPH oxidase, did not decrease RhoA
activation but inhibited TGF-?1-induced ?-SMA and Fn-EIIIA expression, indicating
that RhoA is upstream of ROS generation. RhoA/ROCK also regulated polymerase
(DNA-directed) ?-interacting protein 2 (Poldip2), a newly discovered Nox4
enhancer protein. Collectively, these data indicate that RhoA/ROCK is upstream of
Poldip2-dependent Nox4 regulation and ROS production and induces redox signaling
of kidney myofibroblast activation and may broader implications in the
pathophysiology of renal fibrosis.
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