scholarly journals NQO1 Deficiency Aggravates Renal Injury by Dysregulating Vps34/ATG14L Complex during Autophagy Initiation in Diabetic Nephropathy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 333
Author(s):  
Geum-Lan Hong ◽  
Kyung-Hyun Kim ◽  
Chul-Ho Lee ◽  
Tae-Won Kim ◽  
Ju-Young Jung
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor Beta ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Cell Damage ◽  
End Stage ◽  
Hk2 Cells ◽  
Tgf Β1

Diabetic nephropathy (DN) is one of the causes of end-stage renal failure, featuring renal fibrosis. However, autophagy, a vital process for intracellular homeostasis, can counteract renal fibrosis. Moreover, NAD(P)H: quinone dehydrogenase 1 (NQO1) modulates the ratios of reduced/oxidized nicotinamide nucleotides, exerting a cytoprotective function. Here, to examine the role of NQO1 genes in DN progression, the levels of autophagy-related proteins and pro-fibrotic markers were assessed in silencing or overexpression of NQO1 in human proximal tubular cells (HK2), and C57BL/6 (wild-type) and Nqo1 knockout (KO) mice injected to streptozotocin (50 mg/kg). NQO1 deficiency impaired the autophagy process by suppressing basal expression of ClassⅢ PI 3-kinase (Vps34) and autophagy-related (ATG)14L and inducing the expressions of transforming growth factor beta (TGF-β1), Smad3, and matrix metallopeptidase9 (MMP9) in high-glucose (HG) -treated HK2 cells. Meanwhile, NQO1 overexpression increased the expression of Vps34 and ATG14L, while, reducing TGF-β1, Smad3 and MMP9 expression. In vivo, the expression of Vps34 and ATG14L were suppressed in Nqo1 KO mice indicating aggravated glomerular changes and interstitial fibrosis. Therefore, NQO1 deficiency dysregulated autophagy initiation in HK2 cells, with consequent worsened renal cell damage under HG condition. Moreover, STZ-treated Nqo1 KO mice showed that NQO1 deficiency aggravated renal fibrosis by dysregulating autophagy.

The role of endoglin in kidney fibrosis

2014 ◽  
Vol 16 ◽  
Author(s):  
Jose M. Muñoz-Felix ◽  
Barbara Oujo ◽  
Jose M. Lopez-Novoa
Keyword(s):  
Transforming Growth Factor Beta ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Cell Types ◽  
Experimental Models ◽  
Kidney Fibrosis ◽  
End Stage

Tubulointerstitial fibrosis and glomerulosclerosis, are a major feature of end stage chronic kidney disease (CKD), characterised by an excessive accumulation of extracellular matrix (ECM) proteins. Transforming growth factor beta-1 (TGF-β1) is a cytokine with an important role in many steps of renal fibrosis such as myofibroblast activation and proliferation, ECM protein synthesis and inflammatory cell infiltration. Endoglin is a TGF-β co-receptor that modulates TGF-β responses in different cell types. In numerous cells types, such as mesangial cells or myoblasts, endoglin regulates negatively TGF-β-induced ECM protein expression. However, recently it has been demonstrated that ‘in vivo’ endoglin promotes fibrotic responses. Furthermore, several studies have demonstrated an increase of endoglin expression in experimental models of renal fibrosis in the kidney and other tissues. Nevertheless, the role of endoglin in renal fibrosis development is unclear and a question arises: Does endoglin protect against renal fibrosis or promotes its development? The purpose of this review is to critically analyse the recent knowledge relating to endoglin and renal fibrosis. Knowledge of endoglin role in this pathology is necessary to consider endoglin as a possible therapeutic target against renal fibrosis.

scholarly journals Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs

2020 ◽  
Vol 11 ◽  
Author(s):  
Hiroko Sakuma ◽  
Shinji Hagiwara ◽  
Phillip Kantharidis ◽  
Tomohito Gohda ◽  
Yusuke Suzuki
Keyword(s):  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Related Factor ◽  
Major Health Problem ◽  
Diabetic Kidney ◽  
End Stage

Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18–22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.

scholarly journals LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 260 ◽  
Author(s):  
Qing Zhang ◽  
Xiaonan Hou ◽  
Bradley Evans ◽  
Jamison VanBlaricom ◽  
Saravut Weroha ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Ascites Formation ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

scholarly journals The Attenuation of Moutan Cortex on Oxidative Stress for Renal Injury in AGEs-Induced Mesangial Cell Dysfunction and Streptozotocin-Induced Diabetic Nephropathy Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Minghua Zhang ◽  
Liang Feng ◽  
Junfei Gu ◽  
Liang Ma ◽  
Dong Qin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Cell Dysfunction ◽  
Moutan Cortex

Oxidative stress (OS) has been regarded as one of the major pathogeneses of diabetic nephropathy (DN) through damaging kidney which is associated with renal cells dysfunction. The aim of this study was to investigate whether Moutan Cortex (MC) could protect kidney function against oxidative stressin vitroorin vivo. The compounds in MC extract were analyzed by HPLC-ESI-MS. High-glucose-fat diet and STZ (30 mg kg−1) were used to induce DN rats model, while 200 μg mL−1AGEs were for HBZY-1 mesangial cell damage. The treatment with MC could significantly increase the activity of SOD, glutathione peroxidase (GSH-PX), and catalase (CAT). However, lipid peroxidation malondialdehyde (MDA) was reduced markedlyin vitroorin vivo. Furthermore, MC decreased markedly the levels of blood glucose, serum creatinine, and urine protein in DN rats. Immunohistochemical assay showed that MC downregulated significantly transforming growth factor beta 2 (TGF-β2) protein expression in renal tissue. Our data provided evidence to support this fact that MC attenuated OS in AGEs-induced mesangial cell dysfunction and also in high-glucose-fat diet and STZ-induced DN rats.

scholarly journals Protective effect of syringaresinol on rats with diabetic nephropathy via regulation of Nrf2/HO-1 and TGF- β1/Smads pathways

2022 ◽  
Vol 20 (2) ◽  
pp. 275-280
Author(s):  
Lei Ji ◽  
Xue Zhong ◽  
Xingxing Xia ◽  
Wei Yu ◽  
Yuping Qin
Keyword(s):  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Protective Effect ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Pathological Changes ◽  
Tgf Β1

Purpose: To investigate the protective role of syringaresinol in a rat model of diabetic nephropathy (DN). Methods: Streptozotocin was injected intraperitoneally into rats to establish the diabetic model. Streptozotocin-induced rats were orally administered syringaresinol, and pathological changes in kidneys were assessed using hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was used to determine kidney injury indicators, 24-h urine proteins, blood urea nitrogen (BUN), and serum creatinine (SCR). Blood glucose was measured using a blood glucose meter, while levels of malonaldehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) in kidney were also measured using ELISA. Results: Pathological changes in the kidneys were observed in rats post-streptozotocin treatment. Administration of syringaresinol reduced the lesion degree, with improved pathological morphology in kidney. Syringaresinol administration significantly attenuated streptozotocin-increased levels of BUN, SCR, 24-h urine protein, and blood glucose (p < 0.01). Streptozotocin-induced oxidative stress, shown by enhanced MDA level and reduced levels of SOD, CAT, and GSH-PX, was reversed in rat kidneys following syringaresinol administration. However, the expression levels of nuclear factor erythropoietin- 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) proteins decreased, while transforming growth factor-beta 1 (TGF-β1) and signal transducer and transcriptional modulator (Smad) 2/3/7 proteins increased in rats post-streptozotocin treatment. Syringaresinol administration reversed the effects of streptozotocin on protein expression of Nrf2, HO-1, TGF-β1, and Smad 2/3/7. Conclusion: Syringaresinol exerted a protective effect against DN through activation of Nrf2 and inactivation of TGF-β1/Smad pathways. Thus, the compound can potentially be developed for management of diabetic nephropathy.

scholarly journals IN VIVO EFFICACY OF TOPICAL BINAHONG (ANREDERA CORDIFOLIA (TEN.) STEENIS) LEAF ETHANOLIC EXTRACT ON TRANSFORMING GROWTH FACTOR-BETA 1 IN INFECTED WOUNDS

2021 ◽  
pp. 99-102
Author(s):  
RIZKI ANDINI NAWAWI ◽  
MUHAMMAD TOTONG KAMALUDDIN ◽  
THEODORUS
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ethanolic Extract ◽  
Bacterial Count ◽  
Treatment Groups ◽  
Infected Wounds ◽  
Growth Factor Beta ◽  
Tgf Β1

Objective: This study’s aim was to assess the efficacy of topical Binahong (Anredera cordifolia (Ten.) Steenis) leaf ethanolic extract administration on serum transforming growth factor-beta 1 (TGF-β1) in infected wounds. Methods: An experimental study, in vivo, was conducted in the Biotechnology Laboratory and Animal House, Faculty of Medicine, Universitas Sriwijaya, Palembang, from July to September 2020. There were 30 male Wistar rats aged 10–12 weeks with excisional wounds infected with Staphylococcus aureus ATCC 25923. The rats were divided into five groups and received three concentrations of Binahong leaf extracts (2.5%, 5%, and 10%), salve base, and povidone iodine 10% topically twice daily for 14 days. Serum was obtained before treatment and after 14 days of treatment. Wound area and bacterial count were also recorded and analyzed. Data analysis was performed using computer software. Results: Wound size and bacterial count were significantly decreased in treatment groups receiving topical Binahong leaf ethanolic extract. No significant increase in serum TGF-β1 was observed in all treatment groups. Conclusion: Topical administration of Binahong leaf ethanolic extract on rats with infected wounds for 14 days did not significantly increase serum TGF-β1.

scholarly journals Effect of TGF-β1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256237
Author(s):  
Youngwoo Choi ◽  
Soyoon Sim ◽  
Dong-Hyun Lee ◽  
Hee-Ra Lee ◽  
Ga-Young Ban ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cysteinyl Leukotriene ◽  
Aspirin Exacerbated Respiratory Disease ◽  
Healthy Control ◽  
Tgf Β1 ◽  
Eosinophil Degranulation

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-β1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-β1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-β1 and urinary LTE4. The function of TGF-β1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-β1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-β1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-β1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-β1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-β1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.

scholarly journals Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage–myofibroblast transition

2020 ◽  
Vol 117 (34) ◽  
pp. 20741-20752 ◽  
Author(s):  
Patrick Ming-Kuen Tang ◽  
Ying-ying Zhang ◽  
Jun Xiao ◽  
Philip Chiu-Tsun Tang ◽  
Jeff Yat-Fai Chung ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Early Stage ◽  
Transcriptional Level ◽  
Pou Domain ◽  
Renal Fibrogenesis ◽  
Tgf Β1

Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage–myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-β1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-β1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.

scholarly journals Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury

2013 ◽  
Vol 305 (4) ◽  
pp. F477-F484 ◽  
Author(s):  
Sarah C. Huen ◽  
Gilbert W. Moeckel ◽  
Lloyd G. Cantley
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Transforming Growth Factor Β1 ◽  
Late Time ◽  
Tgf Β1

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

scholarly journals SKLB023 hinders renal interstitial fibrosis in obstructive nephropathy by interfering TGF-β1/Smad3 signaling

RSC Advances ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. 5891-5896 ◽  
Author(s):  
Yanhuan Feng ◽  
Jun Xu ◽  
Fan Guo ◽  
Rongshuang Huang ◽  
Min Shi ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Therapeutic Strategy ◽  
Interstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
The Novel ◽  
Renal Interstitial Fibrosis ◽  
Molecule Inhibitor ◽  
Tgf Β1

The novel small-molecule inhibitor of iNOS (SKLB023) hindered renal interstitial fibrosis in vivo and in vitro by interfering with TGF-β1/Smad3 signaling, highlighting that SKLB023 has potential in the therapeutic strategy for renal fibrosis.

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