stilbenes and Ureteral-Obstruction

Pterostilbene (PTB) is a derivative of resveratrol present in grapes and blueberries. PTB is structurally similar to resveratrol, possessing properties such as being analgesic, anti-aging, antidiabetic, anti-inflammatory, anti-obesity, anti-oxidation, cholesterol-reductive, and neuroprotective. However, there have not been reports on the effect of PTB on macrophage-myofibroblast transition (MMT) induced fibrosis in kidney. In this study, we investigated the antifibrotic effects of PTB on the

Topics: Animals; Blueberry Plants; Disease Models, Animal; Fibrosis; Kidney; Macrophages; Mice, Inbred C57BL; Myofibroblasts; Phytotherapy; Stilbenes; Ureteral Obstruction

This study was performed to assess the effect of resveratrol on the expression of eukaryotic initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4) in renal tissues of rats with unilateral ureteral obstruction (UUO).. Using UUO animal model, after 14 days of surgery, pathological changes were detected by HE staining, renal tubular damage index, renal interstitial collagen deposition area were evaluated by Masson staining, in situ cell apoptosis in renal tissue was analyzed by TUNEL assay, and protein expression of eIF2α and ATF4 in renal tissue was analyzed using western blot detection.. After comparison of the treatment groups with model group, we observed that the degree of renal tubular damage, relative area of renal interstitial collagen and eIF2α, ATF4 protein expression were also significantly reduced (p<0.05, p  <0.01) in the high-dose resveratrol group.. Resveratrol can reduce the level of eIF2α protein expression, which further reduces the ATF4 levels.

Topics: Animals; Eukaryotic Initiation Factor-2; Fibrosis; Kidney; Male; Rats; Rats, Wistar; Resveratrol; Stilbenes; Ureteral Obstruction

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.

Topics: Animals; Biomarkers; Down-Regulation; Epithelial-Mesenchymal Transition; Extracellular Matrix Proteins; Fibrosis; Gene Expression Regulation, Enzymologic; Histone Deacetylases; Kidney; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; p38 Mitogen-Activated Protein Kinases; Stilbenes; Ureteral Obstruction

Renal fibrosis is a common outcome of chronic kidney disease. This study was designed to examine the protective effects of resveratrol (RSV) against renal fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the potential mechanism involved.. Mice were randomly divided into three groups: sham-operated, UUO, and UUO/RSV (20 mg·kg(-1)·day(-1)). Histological changes were examined using periodic acid-Schiff and Masson's trichrome staining after 14 days. Superoxide dismutase (SOD), malondialdehyde (MDA), and 8-OHdG levels were determined using a commercially available kit. ICAM-1, TNF-α, and TGF-β levels were measured using real-time PCR. Fibronectin levels were measured by western blot, and the Smad3 acetylation and Sirt1 were examined by immunoprecipitation and western blot.. Our study showed that RSV treatment significantly attenuated renal injury including extracellular matrix deposition and tubulointerstitium damage. Renal cortical mRNA levels of ICAM-1, TNF-α, and TGF-β, protein expression of fibronectin and Smad3 acetylation were significantly upregulated in the UUO group. However, treatment with RSV significantly decreased the expression of these proteins. Furthermore, RSV also decreased the levels of reactive oxygen species (ROS) including MDA and 8-OHdG, and increased the level of SOD, which protects cells against ROS damage.. Our findings suggest that RSV treatment inhibits oxidative stress, Smad3 acetylation, and renal interstitial fibrosis. Therefore, RSV may have potential as a therapeutic target for the treatment of chronic kidney disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Deoxyguanosine; Fibronectins; Fibrosis; Intercellular Adhesion Molecule-1; Kidney; Kidney Glomerulus; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Reactive Oxygen Species; Resveratrol; Smad3 Protein; Stilbenes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ureteral Obstruction

Epithelial-to-mesenchymal transition (EMT), a biologic process in which tubular cells lose their epithelial phenotypes and acquire new characteristic features of mesenchymal properties, is increasingly recognized as an integral part of renal tissue fibrogenesis. Recent studies indicate that resveratrol, a botanical compound derived mainly from the skins of red grapes, may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. In the present study, we identified that resveratrol inhibits the induction of EMT and deposition of extracellular matrix (ECM) through antagonizing the hedgehog pathway in vitro and in vivo. In rats with unilateral ureteral obstruction (UUO), administration of resveratrol (20mg/kg/day) significantly reduced serum creatinine. Resveratrol also decreased expression of TGF-β1, and inhibited the phenotypic transition from epithelial cells to mesenchymal cells, and the deposition of ECM in UUO rats. In cultured renal tubular epithelial cells (NRK-52E), TGF-β1-induced EMT and ECM synthesis was abolished with the treatment of resveratrol. The induction of EMT was associated with the activation of the hedgehog pathway. Resveratrol treatment markedly inhibited the over-activity of the hedgehog pathway in the obstructed kidney and in TGF-β1-treated NRK-52E cells, resulted in reduction of cellular proliferation, EMT and ECM accumulation. Thus, these results suggest that resveratrol is able to inhibit EMT and fibrosis in vivo and in vitro through antagonizing the hedgehog pathway, and resveratrol may have therapeutic potential for patients with fibrotic kidney diseases.

Topics: Animals; Cell Line; Disease Models, Animal; Epithelial-Mesenchymal Transition; Extracellular Matrix; Fibrosis; Hedgehog Proteins; Kidney; Kidney Tubules; Male; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Resveratrol; Signal Transduction; Smoothened Receptor; Stilbenes; Transforming Growth Factor beta1; Ureteral Obstruction

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/- mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/- mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.

Topics: Animals; Apoptosis; Cells, Cultured; Cyclooxygenase 2; Fibrosis; Heterocyclic Compounds, 4 or More Rings; Kidney Medulla; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Resveratrol; Sirtuin 1; Stilbenes; Ureteral Obstruction