Suppressors of Cytokine Signaling Regulate Angiotensin II-Activated Janus Kinase-Signal Transducers and Activators of Transcription Pathway in Renal Cells

Hernández-Vargas, Purificación; López-Franco, Óscar; Sanjuán, Guillermo; Rupérez, Mónica; Ortiz-Muñoz, Guadalupe; Suzuki, Yusuke; Aguado-Roncero, Pablo; Pérez-Tejerizo, Gloria; Blanco, Julia; Egido, Jesús; Ruíz-Ortega, Marta; Gómez-Guerrero, Carmen

doi:10.1681/asn.2004050374

Cited by 45 publications

(50 citation statements)

References 46 publications

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“…It has been well established that JAK/STAT pathway plays an important role in the proliferation of cells and in the production of TGF-b1 in diabetic nephropathy in vitro and in vivo, [24][25][26] we also confirmed this in our present investigation. However, we found that the increased phosphorylation of JAK2, STAT1 and STAT3 induced by HG was attenuated in all of the different combinations of probucol concentrations and exposure times.…”

Section: Discussionsupporting

confidence: 89%

Janus Kinase 2/Signal Transducers and Activators of Transcription Signal Inhibition Regulates Protective Effects of Probucol on Mesangial Cells Treated with High Glucose

Wang

Liu

et al. 2010

Biological & Pharmaceutical Bulletin

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High glucose activates intracellular signaling processes, including the polyol pathway and the generation of reactive oxygen species (ROS). These pathways further activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway in glomerular mesangial cells. 1-3)The JAK/STAT pathway responds to intracellular ROS, oxidative stress may be a major contributor to diabetes and diabetic nephropathy. [4][5][6][7] The activation of JAK/STAT pathway is essential for high glucose-induced glomerular mesangial cell growth. It also contributes greatly to the production of the cytokine transforming growth factor-b1 (TGF-b1) and extracellular matrix proteins, which contribute to diabetic nephropathy. 1,3,8) Probucol is a drug used clinically for lowering cholesterol with anti-oxidant and anti-proliferative effects. Also, it is a potential inhibitor of DNA damage. 9,10) Recent studies suggest that probucol may be used for the prevention of type-2 diabetes by preventing the increases in aldose reductase, and partly arrested proteinuria and disease progression in glomerulonephritis in rats. [10][11][12][13] It also exerted multiple beneficial morphological effects, including reduced cardiac fibrosis and cardiac apoptosis in rat models. 14)Glomerular mesangial cells have a central role in maintaining the structure and function of the glomerular capillary tuft. High glucose-induced growth of glomerular mesangial cells is a characteristic feature of diabetes-induced renal complications. 1,15,16) Mesangial cells cultured under high glucose conditions produce TGF-b1, connective tissue growth factor (CTGF) and extracellular matrix molecules at a significantly faster rate than those cultured under normal glucose conditions, which is one of the basic underlying mechanisms of diabetic nephropathy and induce persistent fibrosis in vivo. [16][17][18][19] To date, there have been no reports on the effect of probucol on the JAK/STAT pathway, the growth of human mesangial cells (HMCs), and the production of TGF-b1 and CTGF in HMCs. In this study, we investigated the effect of probucol on HMCs cultured under high glucose conditions, and also investigated the molecular mechanisms underlying this effect. Cell Culture Primary HMCs were seeded in 25-cm 2 tissue culture flasks in Mesangial Cell Medium under normal glucose (NG, 5.5 mmol/l glucose), high glucose (HG, 25 mmol/l glucose), or control (5.5 mmol/l glucoseϩ19.5 mmol/l mannitol) conditions. The culture medium was supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 mg/ml streptomycin in a 5% CO 2 atmosphere. The cell medium was changed every other day until the cells became confluent. Cells in passages 3-6 were used. The HMCs at about 70-80% confluence, were cultured in serum-free 1640 with NG for 24 h to synchronize the cell Nephrology, Daqing Oilfield General Hospital; Daqing 163000, P. R. China. Received November 15, 2009; accepted January 28, 2010; published online February 2, 2010 Probucol is a cholesterol-lowering drug with an anti-p...

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Section: Discussionsupporting

confidence: 89%

Janus Kinase 2/Signal Transducers and Activators of Transcription Signal Inhibition Regulates Protective Effects of Probucol on Mesangial Cells Treated with High Glucose

Wang

Liu

et al. 2010

Biological & Pharmaceutical Bulletin

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“…PEI-NPs are polymers that have been reported to effectively deliver oligonucleotides for modulating target gene expression in the kidney, as well as being considered preferable in preparing nonviral vectors because of their long-term safety and biocompatibility. 32,33,36,37 This study found that PEI-NPs were effective in delivering miR-146a to the kidneys, significantly increasing miR-146a expression. In addition, they did not increase the interferon response in obstructed kidneys.…”

Section: Discussionmentioning

confidence: 64%

“…31 Based on these findings, we hypothesized that miR-146a might strongly inhibit renal fibrosis by inhibiting the TGF-β 1 -Smad signaling pathway and inflammation in the kidney. To test this hypothesis, we used polyethylenimine (PEI) nanoparticles (NPs) (in vivo-jetPEI ® ), which have been reported effective in delivering oligonucleotides to the kidneys, 32,33 to deliver synthetic miR-146a to the kidneys in vivo. Using a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO), we tested the effects of miR-146 overexpression on renal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo

Morishita¹,

Imai²,

Yoshizawa³

et al. 2015

IJN

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Renal fibrosis is the final common pathway leading to end-stage renal disease. Although microRNA (miR) was recently shown to be involved in the development of renal fibrosis, few studies have focused on the effects on renal fibrosis of exogenous miR delivered in an in vivo therapeutic setting. The study reported here investigated the effects of miR-146a delivery using polyethylenimine nanoparticles (PEI-NPs) on renal fibrosis in vivo. PEI-NPs bearing miR-146 or control-miR (nitrogen/phosphate ratio: 6) were injected into the tail vein of a mouse model of renal fibrosis induced by unilateral ureteral obstruction. PEI-NPs bearing miR-146 significantly enhanced miR-146a expression in the obstructed kidney compared with the control group, while inhibiting the renal fibrosis area, expression of alpha-smooth muscle actin, and infiltration of F4/80-positive macrophages into the obstructed kidney. In addition, PEI-NPs bearing miR-146a inhibited the transforming growth factor beta 1–Smad and tumor necrosis factor receptor-associated factor 6–nuclear factor kappa B signaling pathways. Control-miR-PEI-NPs did not show any of these effects. These results suggest that the delivery of miR-146a attenuated renal fibrosis by inhibiting pro-fibrotic and inflammatory signaling pathways and that the delivery of appropriate miRs may be a therapeutic option for preventing renal fibrosis in vivo.

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“…In vitro studies Primary mouse mesangial cells (MC), vascular smooth muscle cells (VSMC) and a proximal tubuloepithelial cell line (MCT) were cultured in medium containing 10% FCS (Life Technologies, Rockville, MD, USA) [21][22][23][24]. Quiescent cells were treated for 90 min with peptides before short-term incubation with high glucose (HG; 30 mmol/l D-glucose, 60 min) or lipopolysaccharide (LPS; 1 μg/ml, 30 min; Sigma-Aldrich, St Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

et al. 2015

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Aims/hypothesis The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis.Methods Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells. Results NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-κB activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-κB-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation. Conclusions/interpretation Peptide-based inhibition of IKK complex formation attenuates NF-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications.

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Suppressors of Cytokine Signaling Regulate Angiotensin II-Activated Janus Kinase-Signal Transducers and Activators of Transcription Pathway in Renal Cells

Abstract: Suppressors of cytokine signaling (SOCS) family is

Cited by 45 publications

References 46 publications

Janus Kinase 2/Signal Transducers and Activators of Transcription Signal Inhibition Regulates Protective Effects of Probucol on Mesangial Cells Treated with High Glucose

Janus Kinase 2/Signal Transducers and Activators of Transcription Signal Inhibition Regulates Protective Effects of Probucol on Mesangial Cells Treated with High Glucose

Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo

Peptide-based inhibition of IκB kinase/nuclear factor-κB pathway protects against diabetes-associated nephropathy and atherosclerosis in a mouse model of type 1 diabetes

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