Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach

Altirriba, Jordi; Barberà, Albert; Zotto, H Del; Nadal, Belén; Piquer, Sandra; Sánchez-Pla, Álex; Gagliardino, Juan José; Gomis, Ramón

doi:10.1186/1471-2164-10-406

Cited by 19 publications

(31 citation statements)

References 49 publications

(60 reference statements)

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“…Hoechst 33258 was used as nuclear marker (Sigma). The use of PCNA for measuring islet proliferation has been validated in previous studies [10,[12][13][14]. Images were taken using a Leica DMR HC epifluorescence microscope and a Leica TCS-SL confocal microscope.…”

Section: Methodsmentioning

confidence: 99%

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The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

et al. 2010

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Aims/hypothesis Transmembrane protein 27 (TMEM27) is a membrane protein cleaved and shed by pancreatic beta cells that has been proposed as a beta cell mass biomarker. Despite reports of its possible role in insulin exocytosis and cell proliferation, its function in beta cells remains controversial. We aimed to characterise the function of TMEM27 in islets and its potential use as a beta cell mass biomarker. Methods To determine TMEM27 function, we studied TMEM27 gene expression and localisation in human healthy and diabetic islets, the correlation of its expression with cell cycle and insulin secretion genes in human islets, its expression in tungstate-treated rats, and the effects of its overproduction on insulin secretion and proliferation in a beta cell line and islets. To elucidate its utility as a beta cell mass biomarker, we studied TMEM27 cleavage in a beta cell line, islets and primary proximal tubular cells. Results TMEM27 mRNA levels in islets are lower in diabetic donors than in controls. Its gene expression correlates with that of insulin and SNAPIN in human islets. TMEM27 expression is downregulated in islets of tungstate-treated rats, which exhibit decreased insulin secretion and increased proliferation. TMEM27 overproduction in a beta cell line and islets significantly enhanced glucose-induced insulin secretion, with modest or no effects on proliferation. Finally, TMEM27 is cleaved and shed by renal proximal tubular cells and pancreatic islets.A. Barbera and R. Gomis contributed equally to this study. Electronic supplementary material The online version of this article

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Section: Methodsmentioning

confidence: 99%

“…Tungstate treatment has been described previously [10]. Briefly, adult male Wistar rats (Charles River, Wilmington, MA, USA) received ad libitum a solution of 2 mg/ml sodium tungstate (Carlo Erba, Rodano, Italy) in deionised water for 6 weeks, whereas untreated rats received deionised water alone.…”

Section: Methodsmentioning

confidence: 99%

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

et al. 2010

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“…Raw data was background-adjusted, normalised and summarised by robust multi-array analysis (RMA) using the Affy package [21]. Raw and processed data were submitted to several quality controls and analysed for statistical differences as described previously [5]. Briefly, analysis was performed with the LIMMA software package available from Bioconductor (www.bioconductor.org) [22], adjusting p values using Benjamini and Hochberg's method to control the false discovery rate at a value <5% [5].…”

Section: Methodsmentioning

confidence: 99%

“…Raw and processed data were submitted to several quality controls and analysed for statistical differences as described previously [5]. Briefly, analysis was performed with the LIMMA software package available from Bioconductor (www.bioconductor.org) [22], adjusting p values using Benjamini and Hochberg's method to control the false discovery rate at a value <5% [5]. Genes were clustered and represented in a heat diagram with dChip software (http:// biosun1.harvard.edu/complab/dchip) [23].…”

Section: Methodsmentioning

confidence: 99%

“…We have shown that this agent can normalise blood glucose levels in streptozotocin (STZ)-treated rats and that this normalisation correlates with increased beta cell proliferation and neogenesis [2][3][4]. Recently, in a global transcriptome analysis, we identified the gene encoding the Raf-1 kinase inhibitor protein 1 (RKIP1) as one of the potential candidate genes involved in the ability of tungstate to modulate pancreatic beta cell mass [5].…”

Section: Introductionmentioning

confidence: 99%

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The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

et al. 2012

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Aims/hypothesis Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. Methods Rkip1 (also known as Pebp1) knockout (Rkip1 −/− ) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment. Results Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2696-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.

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In vivo sodium tungstate treatment prevents E‐cadherin loss induced by diabetic serum in HK‐2 cell line

Bertinat

Silva

Mann

et al. 2015

Journal Cellular Physiology

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Diabetic nephropathy (DN) is characterized by interstitial inflammation and fibrosis, which is the result of chronic accumulation of extracellular matrix produced by activated fibroblasts in the renal tubulointerstitium. Renal proximal tubular epithelial cells (PTECs), through the process of epithelial-to-mesenchymal transition (EMT), are the source of fibroblasts within the interstitial space, and loss of E-cadherin has shown to be one of the earliest steps in this event. Here, we studied the effect of the anti-diabetic agent sodium tungstate (NaW) in the loss of E-cadherin induced by transforming growth factor (TGF) β-1, the best-characterized in vitro EMT promoter, and serum from untreated or NaW-treated diabetic rats in HK-2 cell line, a model of human kidney PTEC. Our results showed that both TGFβ-1 and serum from diabetic rat induced a similar reduction in E-cadherin expression. However, E-cadherin loss induced by TGFβ-1 was not reversed by NaW, whereas sera from NaW-treated rats were able to protect HK-2 cells. Searching for soluble mediators of NaW effect, we compared secretion of TGFβ isoforms and vascular endothelial growth factor (VEGF)-A, which have opposite actions on EMT. One millimolar NaW alone reduced secretion of both TGFβ-1 and -2, and stimulated secretion of VEGF-A after 48 h. However, these patterns of secretion were not observed after diabetic rat serum treatment, suggesting that protection from E-cadherin loss by serum from NaW-treated diabetic rats originates from an indirect rather than a direct effect of this salt on HK-2 cells, via a mechanism independent of TGFβ and VEGF-A functions.

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Molecular mechanisms of tungstate-induced pancreatic plasticity: a transcriptomics approach

Cited by 19 publications

References 49 publications

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

In vivo sodium tungstate treatment prevents E‐cadherin loss induced by diabetic serum in HK‐2 cell line

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