Piceatannol Attenuates Renal Fibrosis Induced by Unilateral Ureteral Obstruction via Downregulation of Histone Deacetylase 4/5 or p38-MAPK Signaling

Abstract

Piceatannol, a resveratrol metabolite, is a phenolic compound found in red wine and grapes. We investigated the effect of piceatannol on renal fibrosis and histone deacetylase (HDAC) expression in a mouse model of unilateral ureteral obstruction (UUO). Fibrosis was established by UUO and piceatannol was intraperitoneally injected for 2 weeks. Piceatannol suppressed extracellular matrix (ECM) protein deposition including collagen type I and fibronectin as well as connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA) in UUO kidneys. However, the expressions of epithelial-mesenchymal transition (EMT) marker genes, such as N-cadherin and E-cadherin, were not changed in the kidneys after UUO. Masson’s trichrome staining and fluorescence immunostaining showed that piceatannol administration attenuated collagen deposition in UUO kidneys. HDAC1, HDAC4, HDAC5, HDAC6, and HDAC10 protein expression was upregulated in UUO kidneys, whereas that of HDAC8 was downregulated. Piceatannol treatment significantly reduced HDAC4 and HDAC5 protein expression. Further, piceatannol attenuated phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) in UUO kidneys, but not that of transforming growth factor beta1-Smad2/3. These results suggest that class I HDACs and class IIa/b HDACs are involved in renal fibrosis development. Piceatannol may be a beneficial therapeutic agent for treating renal fibrosis via reduction of HDAC4 and HDAC5 protein expression or suppression of the p38-MAPK signaling pathway.

Resveratrol suppresses the myofibroblastic phenotype and fibrosis formation in kidneys via proliferation‐related signalling pathways

“…As a result, resveratrol reduced the production of ECM components, including vimentin and type I and III collagen, thereby attenuating tubulointerstitial fibrosis in kidneys following injury (Figure c–e). Further study showed that resveratrol also significantly inhibited the up‐regulation of Rac1 and N‐cadherin and the down‐regulation of E‐cadherin in UUO rats at the protein level (Figure e,f,h), a finding that was consistent with previous reports (Choi et al, ; Wang, Wang, et al, ; Wang, Zhou, et al, ). EMT is characterized by the loss of epithelial cell polarity and cell‐to‐cell adhesion and increased mesenchymal cell migration, and it is associated with renal fibrosis (Qi, Chen, Poronnik, & Pollock, ; Strutz & Zeisberg, ).…”

HDAC5 Expression in Urothelial Carcinoma Cell Lines Inhibits Long-Term Proliferation but Can Promote Epithelial-to-Mesenchymal Transition

“…While the involvement of HDAC5 in EMT is overall poorly studied to date, in accord with our findings, upregulation of HDAC5 was reported to promote EMT in non-small cell lung cancer cells [21]. Moreover, HDAC5 and HDAC4 were both upregulated in a model of renal fibrosis and suggested to contribute to its pathogenesis [22]. Major regulators of renal fibrosis are TGFβ [23] and TNFα [24].…”

METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial–mesenchymal transition of renal tubular cells in diabetic kidney disease

“…Also, HDAC5 overexpression promoted EMT of renal tubular cells, indicated in E-cadherin downregulation and α-SMA upregulation. Similarly, Choi et al found that piceatannol suppressed renal fibrosis, shown as decreased ECM protein, reduced connective tissue growth factor (CTGF) and α-SMA in UUO kidneys, accompanied with reduced HDAC4 and HDAC5 protein expression 16 . As well known, EMT was the important characteristic of tumor to regulate invasion and metastasis, and HDAC5 was also reported to mediate EMT of tumor cells.…”