RAGE, vascular tone and vascular disease

Farmer, David G.S.; Kennedy, Simon

doi:10.1016/j.pharmthera.2009.06.013

Cited by 91 publications

(62 citation statements)

References 111 publications

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“…To address this issue, we used a monoclonal antibody directed against the RAGE immunoglobulin domains (anti-RAGE) and sRAGE, a truncated form of the receptor spanning the extracellular domain of human RAGE, to inhibit the putative interaction between psoriasin and RAGE on the cell surface. Since sRAGE does not act on the receptor itself, but its ligands, treatment with sRAGE informs us of the consequences of reducing the bioavailability of the ligand as opposed to the consequences of preventing RAGE signal transduction [36]. By blocking RAGE-psoriasin interactions, a significant suppression of the psoriasin-induced increase in cell proliferation and tube formation were demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

Shubbar

Vegfors

Carlström

et al. 2011

Breast Cancer Res Treat

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Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ (DCIS), psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of VEGF and inhibited tumour Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

Shubbar

Vegfors

Carlström

et al. 2011

Breast Cancer Res Treat

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“…RAGE is a 35 kDa polypeptide of the Ig superfamily that plays a critical role in the development of diabetic vascular complications [34,35]. RAGE is present in minimal quantities in the normal endothelial cells and pericytes of the BNB, but is upregulated in a positive-feedback manner when AGE ligands accumulate [24,36].…”

Section: Discussionmentioning

confidence: 99%

“…These activities may induce inflammatory responses, leading to aggravation of diabetic vascular complications [36]. RAGE has also been reported to activate transcription factor nuclear factor κB cells (NF-κB), thus leading to increase production of the cytokines including TNF-α [34,35]. Several studies have demon- g Claudin-5 protein was increased after pretreatment with anti-VEGF neutralising antibody.…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

et al. 2011

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Aims/hypothesis The breakdown of the blood-nerve barrier (BNB) is considered to be a key step in diabetic neuropathy. Although basement membrane hypertrophy and breakdown of the BNB are characteristic features of diabetic neuropathy, the underlying pathogenesis remains unclear. The purpose of the present study was to identify the possible mechanisms responsible for inducing the hypertrophy of basement membrane and the disruption of the BNB after exposure to AGEs. Methods The newly established human peripheral nerve microvascular endothelial cell (PnMEC) and pericyte cell lines were used to elucidate which cell types constituting the BNB regulate the basement membrane and to investigate the effect of AGEs on the basement membrane of the BNB using western blot analysis. Results Fibronectin, collagen type IV and tissue inhibitor of metalloproteinase (TIMP-1) protein were produced mainly by peripheral nerve pericytes, indicating that the basement membrane of the BNB is regulated mainly by these cells. AGEs reduced the production of claudin-5 in PnMECs by increasing autocrine signalling through vascular endothelial growth factor (VEGF) secreted by the PnMECs themselves.Furthermore, AGEs increased the amount of fibronectin, collagen type IV and TIMP-1 in pericytes through a similar upregulation of autocrine VEGF and transforming growth factor (TGF)-β released by pericytes. Conclusions/interpretation These results indicate that pericytes may be the main regulators of the basement membrane at the BNB. AGEs induce basement membrane hypertrophy and disrupt the BNB by increasing autocrine VEGF and TGF-β signalling by pericytes under diabetic conditions.

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“…doi: 10.1681 Pathogenic stimuli in patients with CKD and type 2 diabetes, including hypertension, obesity, heightened renin-angiotensin activity, and albuminuria, activate oxidative stress-mediated inflammation. [1][2][3][4][5] Indeed, oxidative stress and impaired antioxidant capacity intensify with progression of CKD, 6,7 and production of reactive oxygen species and oxidative stress result in activation of the transcription factor nuclear factor kB (NFkB). NFkB regulates expression of proinflammatory cytokines and chemokines, and its pathologic activation is a hallmark of many inflammatory disorders, including CKD.…”

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confidence: 99%

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Reisman

Chertow

Hebbar

et al. 2012

Journal of the American Society of Nephrology

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Inflammation and oxidative stress are hallmarks and mediators of the progression of CKD. Bardoxolone methyl, a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant and anti-inflammatory response, increases estimated GFR and decreases BUN, serum phosphorus, and uric acid concentrations in patients with moderate to severe CKD. However, it also increases albuminuria, which is associated with inflammation and disease progression. Therefore, we investigated whether this bardoxolone methyl-induced albuminuria may result from the downregulation of megalin, a protein involved in the tubular reabsorption of albumin and lipid-bound proteins. Administration of bardoxolone methyl to cynomolgus monkeys significantly decreased the protein expression of renal tubular megalin, which inversely correlated with the urine albuminto-creatinine ratio. Moreover, daily oral administration of bardoxolone methyl to monkeys for 1 year did not lead to any adverse effects on renal histopathologic findings but did reduce serum creatinine and BUN, as observed in patients with CKD. Finally, the bardoxolone methyl-induced decrease in megalin corresponded with pharmacologic induction of renal Nrf2 targets, including NAD(P)H:quinone oxidoreductase 1 enzyme activity and glutathione content. This result indicates that Nrf2 may have a role in megalin regulation. In conclusion, these data suggest that the increase in albuminuria that accompanies bardoxolone methyl administration may result, at least in part, from reduced expression of megalin, which seems to occur without adverse effects and with strong induction of Nrf2 targets. 23: 166323: -167323: , 201223: . doi: 10.1681 Pathogenic stimuli in patients with CKD and type 2 diabetes, including hypertension, obesity, heightened renin-angiotensin activity, and albuminuria, activate oxidative stress-mediated inflammation. [1][2][3][4][5] Indeed, oxidative stress and impaired antioxidant capacity intensify with progression of CKD, 6,7 and production of reactive oxygen species and oxidative stress result in activation of the transcription factor nuclear factor kB (NFkB). NFkB regulates expression of proinflammatory cytokines and chemokines, and its pathologic activation is a hallmark of many inflammatory disorders, including CKD. Activated NFkB is present in the kidneys of patients with diabetic nephropathy but is undetectable in normal healthy kidneys. 8 Thus, oxidative stress facilitates proinflammatory signaling, which frequently results in further oxidative stress, thereby creating a destructive feedback loop and, often, perturbation of normal physiologic processes and disease progression. J Am Soc NephrolTo respond to oxidative and electrophilic stimuli, organisms have developed elaborate cytoprotective pathways that are directly regulated by the

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RAGE, vascular tone and vascular disease

Cited by 91 publications

References 111 publications

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

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