scholarly journals Effects of Retinoids on the TGF-β System and Extracellular Matrix in Experimental Glomerulonephritis

2001 ◽  
Vol 12 (11) ◽  
pp. 2300-2309 ◽  
Author(s):  
CHRISTIAN MORATH ◽  
CLAUDIUS DECHOW ◽  
INGO LEHRKE ◽  
VOLKER HAXSEN ◽  
RÜDIGER WALDHERR ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Retinoic Acid ◽  
Extracellular Matrix Proteins ◽  
Matrix Proteins ◽  
Trans Retinoic Acid ◽  
Experimental Glomerulonephritis ◽  
All Trans Retinoic Acid ◽  
Tgf Β1 ◽  
Glomerular Damage

Abstract. Transforming growth factor—β1 (TGF-β1) overexpression plays a key role in the glomerular accumulation of extracellular matrix proteins in renal disease. Retinoids have previously been shown to significantly limit glomerular damage in rat experimental glomerulonephritis. Therefore, the effects of all-trans retinoic acid and isotretinoin on the components of the TGF-β system and extracellular matrix proteins in anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans retinoic acid or 40 mg/kg body wt isotretinoin (n= 9 per group) either with a pretreatment (day -2 through 8) or posttreatment protocol (day +3 through 8),i.e., starting before or after induction of Thy-GN, respectively. Urinary TGF-β1 excretion was 60% lower in all-trans retinoic acid-treated animals with Thy-GN (P< 0.025). The increase of cortical TGF-β1 gene expression in Thy-GN rats was significantly attenuated with all-trans retinoic acid and even more with isotretinoin treatment as compared with untreated animals (P< 0.025). Cortical expression of TGF receptor II, but not receptor I gene expression, was significantly lower in animals treated with all-trans retinoic acid or isotretinoin (P< 0.05). In all-trans retinoic acid—treated animals with Thy-GN, the increase of glomerular TGF-β1 protein (P< 0.008) and TGF-β1 (P< 0.025) and TGF receptor II mRNA (P< 0.015) was significantly less. Immunohistochemistry revealed less glomerular staining for TGF-β1 and TGF receptor II in the presence of all-trans retinoic acid. TGF-β1 immunostaining was not restricted to monocytes and macrophages, as indicated by double-staining. Glomerular staining for collagen IV and collagen III was less in animals treated with isotretinoin (P< 0.02 for both) in contrast to all-trans retinoic acid, whereas fibronectin remained unchanged. It was concluded that the beneficial effects of retinoids on glomerular damage are presumably due to a marked reduction in renal TGF-β1 and TGF receptor II expression.

scholarly journals All-trans retinoic acid regulating angiopoietins-1 and alleviating extracellular matrix accumulation in interstitial fibrosis rats

Renal Failure ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 658-663
Author(s):  
Zhiqing Zhong ◽  
Hong-Yan Li ◽  
Hongzhen Zhong ◽  
Wenshan Lin ◽  
Shujun Lin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Retinoic Acid ◽  
Interstitial Fibrosis ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Matrix Accumulation

scholarly journals DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 397 ◽  
Author(s):  
Krysta Coyle ◽  
Cheryl Dean ◽  
Margaret Thomas ◽  
Dejan Vidovic ◽  
Carman Giacomantonio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Triple Negative ◽  
Atra Treatment ◽  
Response Elements ◽  
Acid Binding Protein ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA in breast cancer without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of effects that was not predictable based on previously hypothesized predictors of response, such as the levels of atRA nuclear shuttling proteins fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2). Transcriptional profiling revealed that atRA induced distinct gene expression changes in the sensitive versus resistant cell lines that were mostly independent of the presence of retinoic acid response elements (RAREs) or peroxisome proliferator response elements (PPREs). Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA, and we utilized these xenografts to refine the profile and identified that as many as 17% of TNBC patients could benefit from atRA treatment. These data illustrate that differential methylation of specific CpGs may be useful biomarkers for predicting the response of patient tumors to atRA treatment.

scholarly journals All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 525 ◽  
Author(s):  
Edith Sierra-Mondragon ◽  
Rafael Rodríguez-Muñoz ◽  
Carmen Namorado-Tonix ◽  
Eduardo Molina-Jijon ◽  
Daniel Romero-Trejo ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Retinoic Acid ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Smooth Muscle Actin ◽  
Kidney Injury ◽  
Alpha Smooth Muscle Actin ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Tgf Β1

Diabetic nephropathy (DN) involves damage associated to hyperglycemia and oxidative stress. Renal fibrosis is a major pathologic feature of DN. The aim of this study was to evaluate anti-fibrogenic and renoprotective effects of all-trans retinoic acid (ATRA) in isolated glomeruli and proximal tubules of diabetic rats. Diabetes was induced by single injection of streptozotocin (STZ, 60 mg/Kg). ATRA (1 mg/Kg) was administered daily by gavage, from days 3–21 after STZ injection. ATRA attenuated kidney injury through the reduction of proteinuria, renal hypertrophy, increase in natriuresis, as well as early markers of damage such as β2-microglobulin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). The following parameters increased: macrophage infiltration, localization of alpha-smooth muscle actin (αSMA)-positive cells in renal tissue, and pro-fibrotic proteins such as transforming growth factor-β (TGF-β1), laminin beta 1 (LAM-β1), and collagens IV and I. Remarkably, ATRA treatment ameliorated these alterations and attenuated expression and nuclear translocation of Smad3, with increment of glomerular and tubular Smad7. The diabetic condition decreased expression of retinoic acid receptor alpha (RAR-α) through phosphorylation in serine residues mediated by the activation of c-Jun N-terminal kinase (JNK). ATRA administration restored the expression of RAR-α and inhibited direct interactions of JNK/RAR-α. ATRA prevented fibrogenesis through down-regulation of TGF-β1/Smad3 signaling.

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