Trichostatin A ameliorates renal tubulointerstitial fibrosis through modulation of the JNK-dependent Notch-2 signaling pathway

• Published in: Scientific reports Vol. 7; no. 1; pp. 14495 - 14
• Main Authors: Tung, Chun-Wu, Hsu, Yung-Chien, Cai, Chang-Jhih, Shih, Ya-Hsueh, Wang, Ching-Jen, Chang, Pey-Jium, Lin, Chun-Liang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.11.2017; Nature Publishing Group
• Subjects: 13/109; 13/89; 13/95; 38/77; 38/90; 692/4022/1585/104; 692/4022/1585/3182; 82/51; 82/80; 96/34; Animal models; Fibronectin; Fibrosis; Histone deacetylase; Humanities and Social Sciences; JNK protein; Kidney diseases; Kidneys; Molecular modelling; multidisciplinary; Rodents; Science; Science (multidisciplinary); Secretase; Signal transduction; Smad2 protein; Transforming growth factor-b1; Trichostatin A
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-15162-6

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.