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Cyclic stretch-induced TGF-?1 and fibronectin expression is mediated by
?1-integrin through c-Src- and STAT3-dependent pathways in renal epithelial
cells
#MMPMID25477471
Hamzeh MT
; Sridhara R
; Alexander LD
Am J Physiol Renal Physiol
2015[Mar]; 308
(5
): F425-36
PMID25477471
show ga
Extracellular matrix (ECM) proteins, including fibronectin, may contribute to the
early development and progression of renal interstitial fibrosis associated with
chronic renal disease. Recent studies showed that ?1-integrin is associated with
the development of renal fibrosis in a murine model of unilateral ureteral
obstruction (UUO). However, the molecular events responsible for
?1-integrin-mediated signaling, following UUO, have yet to be determined. In this
study, we investigated the mechanism by which mechanical stretch, an in vitro
model for chronic obstructive nephropathy, regulates fibronectin and transforming
growth factor-?1 (TGF-?1) expression in cultured human proximal tubular
epithelium (HK-2) cells. Mechanical stretch upregulated fibronectin and TGF-?1
expression and activated signal transducer and transcription factor 3 (STAT3) in
a time-dependent manner. Stretch-induced fibronectin and TGF-?1 were suppressed
by a STAT3 inhibitor, S3I-201, and by small interfering RNA (siRNA) targeting
human STAT3 (STAT3 siRNA). Similarly, fibronectin and TGF-?1 expression and STAT3
activation induced by mechanical stretch were suppressed by the Src family kinase
inhibitor PP2 and by transfection of HK-2 cells with a dominant-negative mutant
of c-Src (DN-Src), whereas PP3, an inactive analog of PP2, had no significant
effect. Furthermore, mechanical stretch resulted in increased ?1-integrin mRNA
and protein levels in HK-2 cells. Furthermore, neutralizing antibody against
?1-integrin and silencing of ?1-integrin expression with siRNAs resulted in
decreased c-Src and STAT3 activation and TGF-?1 and fibronectin expression evoked
by mechanical stretch. This work demonstrates, for the first time, a role for
?1-integrin in stretch-induced renal fibrosis through the activation of c-Src and
STAT3 signaling pathways.
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