Role played by Disabled-2 in albumin induced MAP Kinase signalling

Diwakar, Ramaswamy; Pearson, Alexander; Colville‐Nash, Paul; Baines, Deborah L.; Dockrell, Mark E. C.

doi:10.1016/j.bbrc.2007.11.171

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…ERK 1/2 also appeared to play a role in CTGF expression in this mesangial cell model as CTGF gene expression was attenuated by ERK inhibition. These observations have been observed in other models of CsA nephrotoxicity [39, 40]. …”

Section: Discussionsupporting

confidence: 80%

Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

O’Connell

Slattery

Ryan

et al. 2012

Journal of Transplantation

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End Stage Renal Disease (ESRD) is an ever increasing problem worldwide. However the mechanisms underlying disease progression are not fully elucidated. This work addressed nephrotoxicity induced by the immunosuppressive agents' cyclosporine A (CsA) and sirolimus (SRL). Nephrotoxicity is the major limiting factor in long term use of CsA. SRL causes less nephrotoxicity than CsA. Therefore investigations into the differential effects of these agents may identify potential mechanisms of nephrotoxicity and means to prevent ESRD induced by therapeutic drugs. Using ELISA, Western blotting, quantitative PCR and a reporter gene assay we detailed the differential effects of CsA and SRL in human renal mesangial cells. CsA treatment increased profibrotic TGF-β1 secretion in human mesangial cells whereas SRL did not, indicating a role for TGF-β in CsA toxicity. However we observed a synergistic nephrotoxic effect when CsA and SRL were co-administered. These synergistic alterations may have been due to an increase in CTGF which was not evident when the immunosuppressive drugs were used alone. The CsA/SRL combination therapy significantly enhanced Smad signalling and altered the extracellular matrix regulator matrix metalloproteinase 9 (MMP-9). Inhibition of the ERK 1/2 pathway, attenuated these CsA/SRL induced alterations indicating a potentially significant role for this pathway.

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Section: Discussionsupporting

confidence: 80%

Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

O’Connell

Slattery

Ryan

et al. 2012

Journal of Transplantation

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“…Overnight exposure of human HKC-8 and porcine LLC-PK1 cells to high concentrations of albumin results in decreased expression of both Dab2 and Akt/PKB as well as megalin (95, 102), without alteration of fluid-phase endocytosis (103). Elevated albumin levels also trigger MAPK pathway activation mediated by upregulation of the epidermal growth factor receptor and induce TGF-β1 secretion via a cascade that requires Dab2 (104, 105). TGF-β1 in turn downregulates megalin and cubilin expression via a Smad2/Smad3-dependent transcriptional response (106).…”

Section: Organization Of the Proximal Tubule Apical Endocytic Pathwaymentioning

confidence: 99%

Receptor-Mediated Endocytosis in the Proximal Tubule

Eshbach

Weisz

2017

Annu. Rev. Physiol.

127

113

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Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular ultrafiltrate to maintain essentially protein-free urine. Compromise of this pathway results in low molecular weight (LMW) proteinuria that can progress to end-stage kidney disease. This review describes our current understanding of the endocytic pathway and the multiligand receptors that mediate LMW protein uptake in PT cells, how these are regulated in response to physiologic cues, and the molecular basis of inherited diseases characterized by LMW proteinuria.

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“…In addition to its effects on Smad signaling, Dab2 appears to play a significant role in transport functions related to other proteins. It binds to megalin (86) and may have important functions related to protein reabsorption by the renal tubule (87); and in its signaling through MAP kinases (88) it could influence albumin-stimulated TGF-beta1 production (89). Axin and its functional homolog, Axil, are limiting components of Wnt signaling through interaction with beta-catenin, the adenomatous polyposis coli gene product (APC), and glycogen synthase kinase 3beta (GSK-3beta) (90–92).…”

Section: Regulation Of Tgf-beta Signalingmentioning

confidence: 99%

TGF-beta signal transduction in chronic kidney disease

Schnaper

Jandeska

Runyan³

et al. 2009

Front Biosci

117

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Transforming growth factor (TGF)-beta is a central stimulus of the events leading to chronic progressive kidney disease, having been implicated in the regulation of cell proliferation, hypertrophy, apoptosis and fibrogenesis. The fact that it mediates these varied events suggests that multiple mechanisms play a role in determining the outcome of TGF-beta signaling. Regulation begins with the availability and activation of TGF-beta and continues through receptor expression and localization, control of the TGF-beta family-specific Smad signaling proteins, and interaction of the Smads with multiple signaling pathways extending into the nucleus. Studies of these mechanisms in kidney cells and in whole-animal experimental models, reviewed here, are beginning to provide insight into the role of TGF-beta in the pathogenesis of renal dysfunction and its potential treatment.

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Role played by Disabled-2 in albumin induced MAP Kinase signalling

Cited by 7 publications

References 29 publications

Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

Receptor-Mediated Endocytosis in the Proximal Tubule

TGF-beta signal transduction in chronic kidney disease

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