Resveratrol attenuates renal injury and fibrosis by inhibiting transforming growth factor-β pathway on matrix metalloproteinase 7

Abstract

Renal injury has a strong relationship to the subsequent development of renal fibrosis. In developing renal fibrosis, tubular epithelial cells in the kidney underwent epithelial-mesenchymal transition (EMT). Matrix metalloproteinase 7 (MMP7) was reported to reduce E-cadherin and induce EMT by up-regulation of β-catenin/lymphoid enhancer-binding factor 1 (LEF1) signaling. In this research, we tried to evaluate the role of resveratrol (RSV) on EMT process in renal injury and fibrosis. Human tubular epithelial cell HK-2 cells were treated with aristolochic acid (AAs) and transforming growth factor-β(TGF-β) to induce EMT with or without the administration of RSV. The inhibitory role of RSV on EMT in renal injury and fibrosis was determined by Western blotting, real-time PCR, and immunofluorescence staining. The EMT repressing role of RSV was also evaluated in vivo by renal ischemia-reperfusion (I/R) injury and unilateral ureteral obstruction (UUO) models. The underlying mechanism was investigated by shRNA interfering MMP7 and sirtuin 1 (SIRT1) expression. The results indicated that RSV reversed human kidney 2 (HK-2) cell EMT, renal I/R injury, and renal fibrosis. MMP7 inhibition was responsible for RSV-induced EMT repression. SIRT1 was up-regulated by RSV inhibited TGF-β pathway on MMP7 via deacetylating Smad4. In conclusion, RSV attenuated renal injury and fibrosis by inhibiting EMT process which was attributed to the fact that the up-regulated SIRT1 by RSV deacetylated Smad4 and inhibited MMP7 expression.

Dietary resveratrol confers apoptotic resistance to oxidative stress in myoblasts

“…Finally, we have found that resveratrol is protective against ROS damage in part by increasing antioxidant production via a Sirt1 mediated mechanism, which suppresses apoptotic signaling from intrinsic and extrinsic mediated pathways, although the intrinsic mitochondrial pathway appears to be more important in myoblasts under a high ROS load. Our data are consistent with studies that have shown that resveratrol mediates antioxidant and anti-apoptotic protection against pathologies including renal cell damage [70], ischemia in neural cells [44], and ischemia-reperfusion in cardiac cells [71], and skeletal muscle cells [18]. We cannot rule out the possibility that myoblasts and myotubes may have different capabilities or regulation of their antioxidant systems with or without resveratrol treatment [22].…”

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

“…Specifically, in lung and ovarian cancers, SIRT1 was shown to repress EMT via cell migration inhibition [41,42]. Furthermore, SIRT1 upregulation, through resveratrol treatment, inhibited EMT in renal injury and fibrosis [43]. In the same vein, we found that SIRT1 downregulation, due to lactate exposure or NAM treatment, increased N-cadherin and vimentin expression in RCC cell lines.…”

Acute Effects of the Consumption of Passiflora setacea Juice on Metabolic Risk Factors and Gene Expression Profile in Humans

“…MMP-7 over-expression regulates chemokine gradients that can lead to severe tissue damage through transepithelial influx of neutrophils [59]. In an in vitro and in vivo study, resveratrol reversed the injury of human epithelial cells and attenuated such injury in mice through the inhibition of MMP-7 expression [60]. Kinase Insert Domain Receptor (KDR) (or Vascular Endothelial Growth Factor Receptor-2, VEGFR2) is a key receptor that promotes Vascular Endothelial Growth Factor (VEGF) to form mitosis and generate vascularization.…”