scholarly journals Inhibition of p300/CBP-Associated Factor Attenuates Renal Tubulointerstitial Fibrosis through Modulation of NF-kB and Nrf2

2019 ◽  
Vol 20 (7) ◽  
pp. 1554 ◽  
Author(s):  
Sungjin Chung ◽  
Soojeong Kim ◽  
Mina Son ◽  
Minyoung Kim ◽  
Eun Koh ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Cell Damage ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Tubulointerstitial Fibrosis ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Associated Factor ◽  
Renal Tubulointerstitial Fibrosis

p300/CBP-associated factor (PCAF), a histone acetyltransferase, is involved in many cellular processes such as differentiation, proliferation, apoptosis, and reaction to cell damage by modulating the activities of several genes and proteins through the acetylation of either the histones or transcription factors. Here, we examined a pathogenic role of PCAF and its potential as a novel therapeutic target in the progression of renal tubulointerstitial fibrosis induced by non-diabetic unilateral ureteral obstruction (UUO) in male C57BL/6 mice. Administration of garcinol, a PCAF inhibitor, reversed a UUO-induced increase in the renal expression of total PCAF and histone 3 lysine 9 acetylation and reduced positive areas of trichrome and α-smooth muscle actin and collagen content. Treatment with garcinol also decreased mRNA levels of transforming growth factor-β, matrix metalloproteinase (MMP)-2, MMP-9, and fibronectin. Furthermore, garcinol suppressed nuclear factor-κB (NF-κB) and pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6, whereas it preserved the nuclear expression of nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and levels of Nrf2-dependent antioxidants including heme oxygense-1, catalase, superoxide dismutase 1, and NAD(P)H:quinone oxidoreductase 1. These results suggest that the inhibition of inordinately enhanced PCAF could mitigate renal fibrosis by redressing aberrant balance between inflammatory signaling and antioxidant response through the modulation of NF-κB and Nrf2.

Co-activation of synovial fibroblasts by laminin-111 and transforming growth factor-β induces expression of matrix metalloproteinases 3 and 10 independently of nuclear factor-κB

2007 ◽  
Vol 67 (4) ◽  
pp. 559-562 ◽  
Author(s):  
K Warstat ◽  
T Pap ◽  
G Klein ◽  
S Gay ◽  
W K Aicher
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Synovial Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
The Matrix ◽  
Specific Tissue ◽  
Significant Expression

We showed previously that the attachment of synovial fibroblasts to laminin (LM)-111 in the presence of transforming growth factor-β induces significant expression of the matrix metalloproteinase (MMP)-3. Here we go on to investigate the regulation of additional MMPs and their specific tissue inhibitors of matrix proteases (TIMPs). Changes in steady-state mRNA levels encoding TIMPs and MMPs were investigated by quantitative reverse transcription–polymerase chain reaction. Production of MMPs was monitored by a multiplexed immunoarray. Signal transduction pathways were studied by immunoblotting. Attachment of synovial fibroblasts to LM-111 in the presence of transforming growth factor-β induced significant increases in MMP-3 mRNA (12.35-fold, p<0.001) and protein (mean 62 ng/ml, sixfold, p<0.008) and in expression of MMP-10 mRNA (11.68-fold, p<0.05) and protein (54 ng/ml, 20-fold, p⩾0.02). All other TIMPs and MMPs investigated failed to show this LM-111-facilitated transforming growth factor-β response. No phosphorylation of nuclear factor-κB was observed. We conclude that co-stimulation of synovial fibroblasts by LM-111 together with transforming growth factor-β suffices to induce significant expression of MMP-3 and MMP-10 by synovial fibroblasts and that this induction is independent of nuclear factor-κB phosphorylation.

scholarly journals Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-deficient mice

2016 ◽  
Vol 310 (7) ◽  
pp. G526-G538 ◽  
Author(s):  
Jelske N. van der Veen ◽  
Susanne Lingrell ◽  
Xia Gao ◽  
Ariel D. Quiroga ◽  
Abhijit Takawale ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Transforming Growth Factor ◽  
Body Weight Gain ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Liver Weight ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Important Enzyme

Phosphatidylethanolamine N-methyltransferase (PEMT) is an important enzyme in hepatic phosphatidylcholine (PC) biosynthesis. Pemt−/− mice are protected against high-fat diet (HFD)-induced obesity and insulin resistance; however, these mice develop nonalcoholic fatty liver disease (NAFLD). We hypothesized that peroxisomal proliferator-activated receptor-γ (PPARγ) activation by pioglitazone might stimulate adipocyte proliferation, thereby directing lipids from the liver toward white adipose tissue. Pioglitazone might also act directly on PPARγ in the liver to improve NAFLD. Pemt+/+ and Pemt−/− mice were fed a HFD with or without pioglitazone (20 mg·kg−1·day−1) for 10 wk. Pemt−/− mice were protected from HFD-induced obesity but developed NAFLD. Treatment with pioglitazone caused an increase in body weight gain in Pemt−/− mice that was mainly due to increased adiposity. Moreover, pioglitazone improved NAFLD in Pemt−/− mice, as indicated by a 35% reduction in liver weight and a 57% decrease in plasma alanine transaminase levels. Livers from HFD-fed Pemt−/− mice were steatotic, inflamed, and fibrotic. Hepatic steatosis was still evident in pioglitazone-treated Pemt−/− mice; however, treatment with pioglitazone reduced hepatic fibrosis, as evidenced by reduced Sirius red staining and lowered mRNA levels of collagen type Iα1 ( Col1a1), tissue inhibitor of metalloproteinases 1 ( Timp1), α-smooth muscle actin ( Acta2), and transforming growth factor-β ( Tgf-β). Similarly, oxidative stress and inflammation were reduced in livers from Pemt−/− mice upon treatment with pioglitazone. Together, these data show that activation of PPARγ in HFD-fed Pemt −/− mice improved liver function, while these mice were still protected against diet-induced obesity and insulin resistance.

l-Theanine prevents carbon tetrachloride-induced liver fibrosis via inhibition of nuclear factor κB and down-regulation of transforming growth factor β and connective tissue growth factor

2015 ◽  
Vol 35 (2) ◽  
pp. 135-146 ◽  
Author(s):  
JE Pérez-Vargas ◽  
N Zarco ◽  
P Vergara ◽  
M Shibayama ◽  
J Segovia ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Hepatic Cirrhosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Tissue Growth ◽  
Nuclear Factor

Here we evaluated the ability of l-theanine in preventing experimental hepatic cirrhosis and investigated the roles of nuclear factor-κB (NF-κB) activation as well as transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) regulation. Experimental hepatic cirrhosis was established by the administration of carbon tetrachloride (CCl4) to rats (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks), and at the same time, adding l-theanine (8.0 mg/kg) to the drinking water. Rats had ad libitum access to water and food throughout the treatment period. CCl4 treatment promoted NF-κB activation and increased the expression of both TGF-β and CTGF. CCl4 increased the serum activities of alanine aminotransferase and γ-glutamyl transpeptidase and the degree of lipid peroxidation, and it also induced a decrease in the glutathione and glutathione disulfide ratio. l-Theanine prevented increased expression of NF-κB and down-regulated the pro-inflammatory (interleukin (IL)-1β and IL-6) and profibrotic (TGF-β and CTGF) cytokines. Furthermore, the levels of messenger RNA encoding these proteins decreased in agreement with the expression levels. l-Theanine promoted the expression of the anti-inflammatory cytokine IL-10 and the fibrolytic enzyme metalloproteinase-13. Liver hydroxyproline contents and histopathological analysis demonstrated the anti-fibrotic effect of l-theanine. In conclusion, l-theanine prevents CCl4-induced experimental hepatic cirrhosis in rats by blocking the main pro-inflammatory and pro-fibrogenic signals.

Leptin is a coactivator of TGF-β in unilateral ureteral obstructive kidney disease

2007 ◽  
Vol 293 (4) ◽  
pp. F1355-F1362 ◽  
Author(s):  
Philipp Kümpers ◽  
Faikah Gueler ◽  
Song Rong ◽  
Michael Mengel ◽  
Irini Tossidou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Target Genes ◽  
Leptin Receptor ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Peptide Hormone ◽  
Tubulointerstitial Fibrosis ◽  
Mrna Levels ◽  
Renal Tubulointerstitial Fibrosis

Progressive tubulointerstitial fibrosis is the common end point leading to end-stage renal disease in experimental and clinical settings. Since the peptide hormone leptin is involved not only in the regulation of obesity but also in the regulation of inflammation and fibrosis, we tested the hypothesis whether leptin deficiency has an impact on tubulointerstitial fibrosis in mice. Leptin-deficient ( ob/ ob) and leptin receptor-deficient mice ( db/ db) were exposed to 14 days of unilateral ureteral obstruction (UUO). The degree of fibrosis and inflammation was compared with that in sham-operated mice by performing immunohistochemistry, quantitative PCR, and Western blotting. We found that tubulointerstitial fibrosis was significantly reduced in the obstructed kidneys of ob/ ob compared with db/ db mice or control mice. Detailed analysis of infiltrating inflammatory cells by immunohistochemistry revealed a significant reduction of CD4+ cells at 14 days after UUO in both ob/ ob and db/ db mice. In contrast, we could not detect significant differences in CD8+ cells and macrophage content. Transforming growth factor (TGF)-β mRNA levels, TGF-β-induced Smad-2/3 activation, and the upregulation of downstream target genes were significantly reduced in ob/ ob mice. In addition, we demonstrated that leptin could enhance TGF-β signaling in normal rat kidney fibroblasts in vitro. We conclude that leptin can serve as a cofactor of TGF-β activation and thus plays an important role in renal tubulointerstitial fibrosis. Therefore, selective blockade of the leptin axis might provide a therapeutic possibility to prevent or delay fibrotic kidney disease.

scholarly journals Hepatocyte nuclear factor 4α and cancer-related cell signaling pathways: a promising insight into cancer treatment

2021 ◽  
Vol 53 (1) ◽  
pp. 8-18
Author(s):  
Duo-Duo Lv ◽  
Ling-Yun Zhou ◽  
Hong Tang
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Critical Factor ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Cellular Processes ◽  
Hepatocyte Nuclear Factor 4Α ◽  
Transcription 3

AbstractHepatocyte nuclear factor 4α (HNF4α), a member of the nuclear receptor superfamily, is described as a protein that binds to the promoters of specific genes. It controls the expression of functional genes and is also involved in the regulation of numerous cellular processes. A large number of studies have demonstrated that HNF4α is involved in many human malignancies. Abnormal expression of HNF4α is emerging as a critical factor in cancer cell proliferation, apoptosis, invasion, dedifferentiation, and metastasis. In this review, we present emerging insights into the roles of HNF4α in the occurrence, progression, and treatment of cancer; reveal various mechanisms of HNF4α in cancer (e.g., the Wnt/β-catenin, nuclear factor-κB, signal transducer and activator of transcription 3, and transforming growth factor β signaling pathways); and highlight potential clinical uses of HNF4α as a biomarker and therapeutic target for cancer.

Sign in / Sign up

Export Citation Format

Share Document