scholarly journals Tangeretin Ameliorates Glucose-Induced Podocyte Injury through Blocking Epithelial to Mesenchymal Transition Caused by Oxidative Stress and Hypoxia

2020 ◽  
Vol 21 (22) ◽  
pp. 8577
Author(s):  
Min-Kyung Kang ◽  
Soo-Il Kim ◽  
Su Yeon Oh ◽  
Woojin Na ◽  
Young-Hee Kang
Keyword(s):  
Oxidative Stress ◽  
Epithelial To Mesenchymal Transition ◽  
Slit Diaphragm ◽  
Ros Production ◽  
Podocyte Injury ◽  
Mesenchymal Transition ◽  
Foot Process Effacement ◽  
In Vivo Animal Model ◽  
Foot Process ◽  
Junction Proteins

Podocyte injury inevitably results in leakage of proteins from the glomerular filter and is vital in the pathogenesis of diabetic nephropathy (DN). The underlying mechanisms of podocyte injury facilitate finding of new therapeutic targets for DN treatment and prevention. Tangeretin is an O-polymethoxylated flavone present in citrus peels with anti-inflammatory and antioxidant properties. This study investigated the renoprotective effects of tangeretin on epithelial-to-mesenchymal transition-mediated podocyte injury and fibrosis through oxidative stress and hypoxia caused by hyperglycemia. Mouse podocytes were incubated in media containing 33 mM glucose in the absence and presence of 1–20 μM tangeretin for up to 6 days. The in vivo animal model employed db/db mice orally administrated with 10 mg/kg tangeretin for 8 weeks. Non-toxic tangeretin inhibited glucose-induced expression of the mesenchymal markers of N-cadherin and α-smooth muscle actin in podocytes. However, the reduced induction of the epithelial markers of E-cadherin and P-cadherin was restored by tangeretin in diabetic podocytes. Further, tangeretin enhanced the expression of the podocyte slit diaphragm proteins of nephrin and podocin down-regulated by glucose stimulation. The transmission electron microscopic images revealed that foot process effacement and loss of podocytes occurred in diabetic mouse glomeruli. However, oral administration of 10 mg/kg tangeretin reduced urine albumin excretion and improved foot process effacement of diabetic podocytes through inhibiting loss of slit junction and adherenes junction proteins. Glucose enhanced ROS production and HIF-1α induction in podocytes, leading to induction of oxidative stress and hypoxia. Similarly, in diabetic glomeruli reactive oxygen species (ROS) production and HIF-1α induction were observed. Furthermore, hypoxia-evoking cobalt chloride induced epithelial-to-mesenchymal transition (EMT) process and loss of slit diaphragm proteins and junction proteins in podocytes, which was inhibited by treating submicromolar tangeretin. Collectively, these results demonstrate that tangeretin inhibited podocyte injury and fibrosis through blocking podocyte EMT caused by glucose-induced oxidative stress and hypoxia.

scholarly journals Tangeretin Ameliorates Podocyte Injury Through Blocking Epithelial to Mesenchymal Transition in High Glucose-exposed Podocytes and Diabetic Kidneys (P06-009-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Min-Kyung Kang ◽  
Young-Hee Kang
Keyword(s):  
Epithelial Cells ◽  
High Glucose ◽  
Epithelial To Mesenchymal Transition ◽  
Kidney Tissue ◽  
Slit Diaphragm ◽  
Podocyte Injury ◽  
Mesenchymal Transition ◽  
Tissue Sections ◽  
Foot Process Effacement ◽  
Foot Process

Abstract Objectives Epithelial to mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties. This process contributes to the accumulation of matrix proteins in kidney and leads to renal glomeruli fibrosis. Tangeretin is an O-polymethoxylated flavone with anti-inflammatory and antioxidant properties that is found in citrus peels. This study investigated the renoprotective effects of tangeretin on EMT-mediated podocyte injury and fibrosis caused by hyperglycemia. Methods Mouse glomerular epithelial cells (podocyte) were incubated in media containing 5.5 mM glucose, 27.5 mM mannitol as an osmotic control or 33 mM glucose (high glucose) in the absence and presence of 1–20 μM tangeretin for up to 4 days. Antibodies of E-cadherin, N-cadherin, α-SMA, nephrin, podocin, P-cadherin and collagen1 were used for Western blotting. The in vivo animal model employed db/db mice orally administrated with 10 mg/kg tangeretin for 8 weeks. Kidney tissue extracts of were Western-blotted, and tissue sections cut down in 5 µM thickness were immunohistochemically stained. In addition, kidney tissue sections (ultrathin sections, 70 nm) were observed with transmission electron microscopy (TEM). Results Non-toxic tangeretin enhanced expression of the podocyte slit diaphragm proteins of nephrin, podocin and P-cadherin down-regulated by glucose stimulation. Also, tangeretin inhibited high glucose-induced expression of the mesenchymal markers of N-cadherin and α-smooth muscle actin, whereas the induction of the epithelial marker E-cadherin was enhanced. Furthermore tangeretin attenuated the fibronectin induction and collagen production elevated by the presence of high glucose. The TEM images revealed that podocyte foot process effacement occurred in diabetic mouse glomeruli. However, oral administration of 10 mg/kg tangeretin reduced urine albumin excretion and improved foot process effacement of diabetic podocytes through inhibiting loss of glomerular slit junction proteins. Conclusions These results demonstrated that tangeretin maintained the structures of podocyte slit diaphragm in a robust form, and inhibited podocyte injury through blocking epithelial to mesenchymal transition of podocytes. Therefore, tangeretin may be a potent renoprotective agent counteracting diabetes-associated loss of podocyte slit diaphragm and maintaining glomerular filtration barrier. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MEST) (NRF-2017R1A6A3A04011473).

scholarly journals Role of NADPH Oxidase-Mediated Reactive Oxygen Species in Podocyte Injury

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Shan Chen ◽  
Xian-Fang Meng ◽  
Chun Zhang
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Epithelial To Mesenchymal Transition ◽  
Kidney Diseases ◽  
Treatment Strategies ◽  
Reactive Oxygen ◽  
Glomerular Sclerosis ◽  
Oxygen Species ◽  
Podocyte Injury ◽  
Mesenchymal Transition

Proteinuria is an independent risk factor for end-stage renal disease (ESRD) (Shankland, 2006). Recent studies highlighted the mechanisms of podocyte injury and implications for potential treatment strategies in proteinuric kidney diseases (Zhang et al., 2012). Reactive oxygen species (ROS) are cellular signals which are closely associated with the development and progression of glomerular sclerosis. NADPH oxidase is a district enzymatic source of cellular ROS production and prominently expressed in podocytes (Zhang et al., 2010). In the last decade, it has become evident that NADPH oxidase-derived ROS overproduction is a key trigger of podocyte injury, such as renin-angiotensin-aldosterone system activation (Whaley-Connell et al., 2006), epithelial-to-mesenchymal transition (Zhang et al., 2011), and inflammatory priming (Abais et al., 2013). This review focuses on the mechanism of NADPH oxidase-mediated ROS in podocyte injury under different pathophysiological conditions. In addition, we also reviewed the therapeutic perspectives of NADPH oxidase in kidney diseases related to podocyte injury.

scholarly journals Activation of Notch1 signaling in podocytes by glucose-derived AGEs contributes to proteinuria

2020 ◽  
Vol 8 (1) ◽  
pp. e001203
Author(s):  
Rajkishor Nishad ◽  
Prajakta Meshram ◽  
Ashish Kumar Singh ◽  
G Bhanuprakash Reddy ◽  
Anil Kumar Pasupulati
Keyword(s):  
Notch Signaling ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Notch1 Signaling ◽  
Reverse Transcription Pcr ◽  
Filtration Barrier ◽  
Foot Process ◽  
Design And Methods

IntroductionAdvanced glycation end-products (AGEs) are implicated in the pathogenesis of diabetic nephropathy (DN). Previous studies have shown that AGEs contribute to glomerulosclerosis and proteinuria. Podocytes, terminally differentiated epithelial cells of the glomerulus and the critical component of the glomerular filtration barrier, express the receptor for AGEs (RAGE). Podocytes are susceptible to severe injury during DN. In this study, we investigated the mechanism by which AGEs contribute to podocyte injury.Research design and methodsGlucose-derived AGEs were prepared in vitro. Reactivation of Notch signaling was examined in AGE-treated human podocytes (in vitro) and glomeruli from AGE-injected mice (in vivo) by quantitative reverse transcription-PCR, western blot analysis, ELISA and immunohistochemical staining. Further, the effects of AGEs on epithelial to mesenchymal transition (EMT) of podocytes and expression of fibrotic markers were evaluated.ResultsUsing human podocytes and a mouse model, we demonstrated that AGEs activate Notch1 signaling in podocytes and provoke EMT. Inhibition of RAGE and Notch1 by FPS-ZM1 (N-Benzyl-4-chloro-N-cyclohexylbenzamide) and DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenyl glycine t-butylester), respectively, abrogates AGE-induced Notch activation and EMT. Inhibition of RAGE and Notch1 prevents AGE-induced glomerular fibrosis, thickening of the glomerular basement membrane, foot process effacement, and proteinuria. Furthermore, kidney biopsy sections from people with DN revealed the accumulation of AGEs in the glomerulus with elevated RAGE expression and activated Notch signaling.ConclusionThe data suggest that AGEs activate Notch signaling in the glomerular podocytes. Pharmacological inhibition of Notch signaling by DAPT ameliorates AGE-induced podocytopathy and fibrosis. Our observations suggest that AGE-induced Notch reactivation in mature podocytes could be a novel mechanism in glomerular disease and thus could represent a novel therapeutic target.

scholarly journals Function of cAMP scaffolds in obstructive lung disease: Focus on epithelial‐to‐mesenchymal transition and oxidative stress

2019 ◽  
Vol 176 (14) ◽  
pp. 2402-2415 ◽  
Author(s):  
Haoxiao Zuo ◽  
Isabella Cattani‐Cavalieri ◽  
Samuel Santos Valença ◽  
Nshunge Musheshe ◽  
Martina Schmidt
Keyword(s):  
Oxidative Stress ◽  
Lung Disease ◽  
Obstructive Lung Disease ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Disease Focus ◽  
And Oxidative Stress

scholarly journals Malic enzyme 1 (ME1) in the biology of cancer: it is not just intermediary metabolism

2020 ◽  
Vol 65 (4) ◽  
pp. R77-R90
Author(s):  
Frank A Simmen ◽  
Iad Alhallak ◽  
Rosalia C M Simmen
Keyword(s):  
Oxidative Stress ◽  
Malic Enzyme ◽  
Epithelial To Mesenchymal Transition ◽  
Cholesterol Biosynthesis ◽  
Intermediary Metabolism ◽  
Therapeutic Approaches ◽  
Mesenchymal Transition ◽  
Epithelial Cancers ◽  
Transcriptional Target

Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated genes in liver and adipose and is a transcriptional target of thyroxine. Multiple studies have since documented that ME1 is pro-oncogenic in numerous epithelial cancers. In tumor cells, the reduction of ME1 gene expression or the inhibition of its activity resulted in decreases in proliferation, epithelial-to-mesenchymal transition and in vitro migration, and conversely, in promotion of oxidative stress, apoptosis and/or cellular senescence. Here, we integrate recent findings to highlight ME1’s role in oncogenesis, provide a rationale for its nexus with metabolic syndrome and diabetes, and raise the prospects of targeting the cytosolic NADPH network to improve therapeutic approaches against multiple cancers.

scholarly journals The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma

2021 ◽  
Vol 22 (22) ◽  
pp. 12216
Author(s):  
Valeria Ramundo ◽  
Giada Zanirato ◽  
Elisabetta Aldieri
Keyword(s):  
Oxidative Stress ◽  
Malignant Pleural Mesothelioma ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Asbestos Exposure ◽  
Transforming Growth Factor Β ◽  
Pleural Mesothelioma ◽  
Mesenchymal Transition ◽  
Pharmacological Approach

Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.

scholarly journals Presence of Stromal Cells Enhances Epithelial-to-Mesenchymal Transition (EMT) Induction in Lung Bronchial Epithelium after Protracted Exposure to Oxidative Stress of Gamma Radiation

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Anna Acheva ◽  
Siamak Haghdoost ◽  
Alice Sollazzo ◽  
Virpi Launonen ◽  
Meerit Kämäräinen
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Dose Rate ◽  
Cell Lines ◽  
Stromal Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Low Dose ◽  
Mesenchymal Transition ◽  
Low Dose Rate ◽  
Stromal Component

The aim of the study was to investigate the role of a microenvironment in the induction of epithelial-to-mesenchymal transition (EMT) as a sign of early stages of carcinogenesis in human lung epithelial cell lines after protracted low-dose rateγ-radiation exposures. BEAS-2B and HBEC-3KT lung cell lines were irradiated with low-dose rateγ-rays (137Cs, 1.4 or 14 mGy/h) to 0.1 or 1 Gy with or without adding TGF-β. TGF-β-treated samples were applied as positive EMT controls and tested in parallel to find out if the radiation has a potentiating effect on the EMT induction. To evaluate the effect of the stromal component, the epithelial cells were irradiated in cocultures with stromal MRC-9 lung fibroblasts. On day 3 post treatment, the EMT markers:α-SMA, vimentin, fibronectin, and E-cadherin, were analyzed. The oxidative stress levels were evaluated by 8-oxo-dG analysis in both epithelial and fibroblast cells. The protracted exposure to low Linear Energy Transfer (LET) radiation at the total absorbed dose of 1 Gy was able to induce changes suggestive of EMT. The results show that the presence of the stromal component and its signaling (TGF-β) in the cocultures enhances the EMT. Radiation had a minor cumulative effect on the TGF-β-induced EMT with both doses. The oxidative stress levels were higher than the background in both epithelial and stromal cells post chronic irradiation (0.1 and 1 Gy); as for the BEAS-2B cell line, the increase was statistically significant. We suggest that the induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure and the presence of stromal component might enhance the effect through free radical production and accumulation.

scholarly journals Hyperglycemia in the absence of cilia accelerates cystogenesis and induces renal damage

2015 ◽  
Vol 309 (1) ◽  
pp. F79-F87 ◽  
Author(s):  
Kelli M. Sas ◽  
Hong Yin ◽  
Wayne R. Fitzgibbon ◽  
Catalin F. Baicu ◽  
Michael R. Zile ◽  
...  
Keyword(s):  
Disease Progression ◽  
Renal Damage ◽  
Epithelial To Mesenchymal Transition ◽  
Gene Array ◽  
Cyst Formation ◽  
Renal Tubules ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Gene Array Analysis ◽  
Foot Process

In polycystic kidney disease (PKD), the rate of cyst formation and disease progression is highly variable. The lack of predictability in disease progression may be due to additional environmental factors or pathophysiological processes called “third hits.” Diabetes is a growing epidemic, and recent studies suggest that PKD patients may be at an increased risk for this disease. We sought to determine if hyperglycemia enhances the initiation and rate of cystogenesis. Tamoxifen was administered to adult Ift88 conditional floxed allele mice to induce cilia loss in the presence of Cre. Subsequent administration of streptozotocin resulted in equivalent hyperglycemia in cilia+ and cilia− mice. Hyperglycemia with loss of cilia increased the rate of cyst formation and cell proliferation. Structural and functional alterations in the kidney, including focal glomerular foot process effacement, interstitial inflammation, formation of primitive renal tubules, polyuria, and increased proteinuria, were also observed in hyperglycemic cilia− mice. Gene array analysis indicated enhanced Wnt and epithelial-to-mesenchymal transition signaling in the kidney of hyperglycemic cilia− mice. These data show that hyperglycemia, in the absence of cilia, results in renal structural and functional damage and accelerates cystogenesis, suggesting that diabetes is a risk factor in the progression of PKD.

scholarly journals Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in kidney

2021 ◽  
Author(s):  
Elia Escasany ◽  
Borja Lanzón ◽  
Almudena García-Carrasco ◽  
Adriana Izquierdo-Lahuerta ◽  
Lucía Torres ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mesenchymal Transition ◽  
Morphological Alterations ◽  
Toxic Species ◽  
Basement Membrane Thickening ◽  
Foot Process

Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor β (TGFβ) is a key player in the development of fibrosis. However, of the three known TGFβ isoforms, only TGFβ1 has an established role in fibrosis, and the pathophysiological relevance of TGFβ2 and TGFβ3 is unknown. Because Tgfβ3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfβ3-knockout mice (Tgfβ3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfβ3+/- mice exhibited incipient renal fibrosis with epithelial-to-mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis showed toxic species such as diacylglycerides and ceramides in Tgfβ3+/- mice, and dysregulated mitochondrial metabolism. Kidney of Tgfβ3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study shows that renal TGFβ3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFβ1.

Sign in / Sign up

Export Citation Format

Share Document