Role for TGF-β in Cyclosporine-Induced Modulation of Renal Epithelial Barrier Function

Feldman, Gemma; Kiely, Breda; Martín, Natalia; Ryan, Grace; McMorrow, Tara; Ryan, Michael P.

doi:10.1681/asn.2006050527

Cited by 45 publications

(45 citation statements)

References 35 publications

(41 reference statements)

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“…Although a limited TGFb 1 secretion is induced by the sole administration of DFMO, this is in any case insufficient to induce the observed enhanced EMT. Levels of TGFb 1 induced by DFMO are in fact the half of those induced by 4.2 mM Cyclosporin administration that proved earlier 23 to be capable to alter paracellular permeability but not EMT. The irrelevance of DFMO-induced TGFb 1 secretion allowed us to look for a possible alternative explanation for the observed enhanced EMT in polyamine-depleted cells.…”

Section: Discussionmentioning

confidence: 72%

See 1 more Smart Citation

Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells

Prunotto

Compagnone

Bruschi

et al. 2010

Laboratory Investigation

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Epithelial-to-mesenchymal transition (EMT) is involved in embryonic development as well as in several pathological conditions. Literature indicates that polyamine availability may affect transcription of c-myc, matrix metalloproteinase (MMP)1, MMP2, TGFb 1 , and collagen type I mRNA. The aim of this study was to elucidate polyamines role in EMT in vitro. Madin-Darby canine kidney (MDCK) cells were subjected to experimental manipulation of intracellular levels of polyamines. Acquisition of mesenchymal phenotype was evaluated by means of immunofluorescence, western blots, and zymograms. MDCK cells were then subjected to 2D gel proteomic study and incorporation of a biotinilated polyamine (BPA). Polyamine endocellular availability modulated EMT process. Polyamine-depleted cells treated with TGFb 1 showed enhanced EMT with a marked decrease of E-cadherin expression at plasma membrane level and an increased expression of mesenchymal markers such as fibronectin and a-smooth muscle actin. Polyamine-depleted cells showed a twofold increased expression of the rough endoplasmic reticulum (ER)-stress proteins GRP78, GRP94, and HSP90 a/b in 2D gels. The latter data were confirmed by western blot analysis. Administration of BPA showed that polyamines are covalently linked, within the cell, to ER-stress proteins. Intracellular polyamine availability affects EMT in MDCK cells possibly through the modulation of ER-stress protein homeostasis.

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Section: Discussionmentioning

confidence: 72%

“…TGFb 1 in the supernatant was dosed at day 5 of treatment through application of a specific ELISA test (Human TGFb 1 Instant ELISA, Bender MedSystems, Wien, Austria). In both cases, positive control was obtained by treatment of MDCK cells with 4.2 mM Cyclosporin as described earlier by Feldman et al 23 …”

Section: Methodsmentioning

confidence: 99%

Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells

Prunotto

Compagnone

Bruschi

et al. 2010

Laboratory Investigation

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“…Although, it is widely accepted that TGFβ signaling pathway induces cell death through Smad-mediated pathways, the distinct role of this signaling pathway has insufficiently investigated [64]. However, the synergetic cooperation Cyclosporine with TGFβ signaling pathway in the modulation of renal paracellular permeability has been confirmed by Feldman and colleagues [65]. In another study, expression of TGFβ has been demonstrated to be enhanced in cisplatin-induced Acute Kidney Injury (AKI) [66].…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Askari¹,

Abdullahi²,

Poortahmasebi³

et al. 2017

Biol syst Open Access

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It is well documented that use of Cisplatin, Lead acetate and Cyclosporine in the chemotherapy and medical interventions is highly associated with nephrotoxicity and interrelated comorbidities. Here, we proposed the possible molecular mechanisms responsible for nephrotoxicity of these compounds. We utilized the microarray dataset GSE59913 consisting of approximately 600 different compounds profiled in up to 8 different tissues. After analysis with GEO2R, gene expression profiles of three aforementioned compounds were integrated with protein-protein interactions (PPI) networks and topological properties of the networks were measured using Cytoscape software. We found several key genes and signaling pathways that seem to be involved in nephrotoxicity of the examined compounds. Myc and Smad4 were identified as principal players of three compounds' nephrotoxicity through various pathways. Our results revealed the critical functions of Il2, Jak-Stat, Mapk-Pi3k, TGFβ and Ca 2+ signaling pathways as well as novel biomarkers that may mediate the nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine. The significantly altered genes in the compound-treated samples were substantially correlated with regulation of cell proliferation, apoptosis, inflammatory responses and homeostatic processes. This study reveals the important hub genes, biological networks and key pathways as well as novel biomarkers involved in nephrotoxicity of Cisplatin, Lead acetate and Cyclosporine.

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“…Another significant factor involved in the progression of chronic interstitial changes is the profibrotic cytokine transforming growth factor beta 1 (TGF-β1). TGF-β1 promotes the development of interstitial fibrosis by inhibiting ECM degradation, stimulating production of ECM proteins by modulating the normal function of tubular epithelial cells and resident interstitial fibroblasts Slattery et al, 2005;Feldman et al, 2007;Hertig et al, 2008). These mechanisms will be disussed in detail below.…”

Section: Calcineurin Inhibitor Toxicitymentioning

confidence: 99%

Mechanisms of Calcineurin Inhibitor Nephrotoxicity in Chronic Allograft Injury

Slattery¹,

Cassidy²,

Johnston³

et al. 2012

Chronic Kidney Disease and Renal Transplantation

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Role for TGF-β in Cyclosporine-Induced Modulation of Renal Epithelial Barrier Function

Cited by 45 publications

References 35 publications

Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells

Endocellular polyamine availability modulates epithelial-to-mesenchymal transition and unfolded protein response in MDCK cells

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

Mechanisms of Calcineurin Inhibitor Nephrotoxicity in Chronic Allograft Injury

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