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Inhibitory effects of fasudil on renal interstitial fibrosis induced by
unilateral ureteral obstruction
#MMPMID26498136
Baba I
; Egi Y
; Utsumi H
; Kakimoto T
; Suzuki K
Mol Med Rep
2015[Dec]; 12
(6
): 8010-20
PMID26498136
show ga
Renal fibrosis is the major cause of chronic kidney disease, and the
Rho/Rho-associated coiled-coil kinase (ROCK) signaling cascade is involved in the
renal fibrotic processes. Several studies have reported that ROCK inhibitors
attenuate renal fibrosis. However, the mechanism of this process remains to be
fully elucidated. The present study assessed the inhibitory effect of fasudil, a
ROCK inhibitor using immunohistochemistry, reverse transcription-quantitative
polymerase chain reaction and western blot analyses, in vivo and in vitro, to
elucidate the mechanisms underlying renal interstitial fibrosis. In mice induced
with unilateral ureteral obstruction (UUO), collagen accumulation, the expression
of fibrosis?associated genes and the content of hydroxyproline in the kidney
increased 3, 7, and 14 days following UUO. Fasudil attenuated the histological
changes, and the production of collagen and extracellular matrix in the UUO
kidney. The expression of ??smooth muscle actin (??SMA) and the transforming
growth factor?? (TGF?)?Smad signaling pathway, and macrophage infiltration were
suppressed by fasudil in the kidneys of the UUO mice. The present study also
evaluated the role of intrinsic renal cells and infiltrated macrophages using
NRK?52E, NRK?49F and RAW264.7 cells. The mRNA and protein expression levels of
collagen I and ??SMA increased in the NRK?52E and NRK?49F cells stimulated by
TGF??1. Hydroxyfasudil, a bioactive metabolite of fasudil, attenuated the
increase in the mRNA and protein expression levles of ??SMA in the two cell
types. However, the reduction in the mRNA expression of collagen I was observed
in the NRK?49F cells only. Hydroxyfasudil decreased the mRNA expression of
monocyte chemoattractant protein?1 (MCP?1) induced by TGF??1 in the NRK?52E
cells, but not in the NRK?49F cells. In the RAW264.7 cells, the mRNA expression
levels of MCP?1, interleukin (IL)?1?, IL?6 and tumor necrosis factor ? were
increased significantly following lipopolysaccharide stimulation, and were not
suppressed by hydroxyfasudil. These data suggested that the inhibition of ROCK
activity by fasudil suppressed the transformation of renal intrinsic cells into
the myofibroblast cells, and attenuated the infiltration of macrophages, without
inhibiting the expression or the activation of cytokine/chemokines, in the
progression of renal interstitial fibrosis.
|1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs &
derivatives/pharmacology/therapeutic use
[MESH]
|Actins/genetics/metabolism
[MESH]
|Animals
[MESH]
|Cell Line
[MESH]
|Cell Movement/drug effects
[MESH]
|Collagen Type I/genetics/metabolism
[MESH]
|Disease Models, Animal
[MESH]
|Fibrosis/drug therapy/*etiology
[MESH]
|Kidney Diseases/etiology/prevention & control
[MESH]
|Kidney/metabolism/*pathology
[MESH]
|Male
[MESH]
|Mice
[MESH]
|Mice, Inbred C57BL
[MESH]
|Protein Kinase Inhibitors/*pharmacology/therapeutic use
[MESH]
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free
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