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Trichostatin A ameliorates renal tubulointerstitial fibrosis through modulation
of the JNK-dependent Notch-2 signaling pathway
#MMPMID29101337
Tung CW
; Hsu YC
; Cai CJ
; Shih YH
; Wang CJ
; Chang PJ
; Lin CL
Sci Rep
2017[Nov]; 7
(1
): 14495
PMID29101337
show ga
Renal fibrosis is the final common pathological feature in a variety of chronic
kidney disease. Trichostatin A (TSA), a histone deacetylase inhibitor, reportedly
attenuates renal fibrosis in various kidney disease models. However, the detailed
molecular action of TSA in ameliorating renal fibrotic injury is not yet fully
understood. In a cultured renal fibroblastic cell model, we showed that TGF-?1
triggers upregulation of ?-SMA and fibronectin, two hallmarks of myofibroblastic
activation. During the course of TGF-?1 treatment, activation of Smad2/3, p38,
ERK, JNK and Notch-2 was also detected. Under the conditions, administration of
TSA significantly decreased TGF-?1-stimulated expression of ?-SMA, fibronectin,
phospho-JNK, and cleaved Notch-2; however, the levels of phospho-Smad2/3,
phospho-p38 and phospho-ERK remained unchanged. Pharmacological inhibition of
different signaling pathways and genetic knockdown of Notch-2 further revealed
JNK as an upstream effector of Notch-2 in TGF-?1-mediated renal fibrosis.
Consistently, we also demonstrated that administration of TSA or a ?-secretase
inhibitor RO4929097 in the mouse model of unilateral ureteral obstruction
significantly ameliorated renal fibrosis through suppression of the JNK/Notch-2
signaling activation. Taken together, our findings provide further insights into
the crosstalk among different signaling pathways in renal fibrosis, and elucidate
the molecular action of TSA in attenuating fibrogenesis.
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