Abstract
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-β1 triggers upregulation of α-SMA and fibronectin, two hallmarks of myofibroblastic activation. During the course of TGF-β1 treatment, activation of Smad2/3, p38, ERK, JNK and Notch-2 was also detected. Under the conditions, administration of TSA significantly decreased TGF-β1-stimulated expression of α-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-β1-mediated renal fibrosis. Consistently, we also demonstrated that administration of TSA or a γ-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.
Highlights
Renal fibrosis is the final pathological process common to all forms of chronic kidney disease[1] and thereby represents an excellent treatment target
Western blot analysis showed that transforming growth factor-β1 (TGF-β1) at the dose of 5 ng/ml substantially increased levels of α-SMA and fibronectin, two hallmarks of activated fibroblasts, in treated cells (Supplementary Fig. S1a), and this concentration of TGF-β1 was suitable for subsequent experiments
TGF-β1 is well recognized as the key mediator that critically drives fibroblast activation and matrix deposition during development of renal fibrosis
Summary
Renal fibrosis is the final pathological process common to all forms of chronic kidney disease[1] and thereby represents an excellent treatment target. TGF-β1 signaling through the Smad-based (canonical) pathway[5,6,7] is believed to play a critical role in the development of renal fibrosis, a growing body of evidence indicates that several non-Smad (non-canonical) pathways stimulated by TGF-β1 are potentially involved in driving fibrosis in progressive kidney disease[8,9,10] Among these TGF-β1-induced non-Smad signaling pathways, three major mitogen-activated protein kinases (MAPKs) pathways (including p38, ERK and JNK) have been suggested to contribute to inflammatory and fibrotic damages of various renal diseases[11,12,13]. On the basis of our findings in vitro and in vivo, we here propose that the JNK/Notch-2 signaling axis is critically involved in TGF-β1-mediated renal fibrosis, and TSA treatment efficiently suppresses the JNK-dependent Notch-2 signaling pathway
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