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John S. D. Chan – One of the best experts on this subject based on the ideXlab platform.

Akio Koizumi – One of the best experts on this subject based on the ideXlab platform.

  • Spontaneous development of ER stress that can lead to diabetes mellitus is associated with higher calcium-independent phospholipase A2 (iPLA2beta) expression: A role for regulation by SREBP-1
    Journal of Biological Chemistry, 2009
    Co-Authors: Xiaoyong Lei, Akio Koizumi, Sheng Zhang, Suzanne E. Barbour, Alan Bohrer, Eric L. Ford, Feroz R. Papa, Sasanka Ramanadham
    Abstract:

    Abstract Our recent studies indicate that ER stress causes INS-1 cell apoptosis by a Ca2+-independent phospholipase A2 (iPLA2β)-mediated mechanism that promotes ceramide generation via sphingomyelin hydrolysis and subsequent activation of the intrinsic pathway. To elucidate the association between iPLA2β and ER stress, we compared β-cell lines generated from wild type (WT) and Akita mice. The Akita Mouse is a spontaneous model of ER stress that develops hyperglycemia/diabetes due to ER stress-induced β-cell apoptosis. Consistent with a pre-disposition to developing ER stress, basal pPERK and activated caspase-3 are higher in the Akita cells than WT cells. Interestingly, basal iPLA2β, mature SREBP-1 (mSREBP-1), phosphorylated Akt, and NSMase are higher, relative abundances of sphingomyelins lower, and mitochondrial membrane potential (∆Ψ) compromised in Akita cells, in comparison with WT cells. Exposure to thapsigargin accelerates ∆Ψ loss and apoptosis of Akita cells and is associated with increases in iPLA2β, mSREBP-1, and NSMase in both WT and Akita cells. Transfection of Akita cells with iPLA2β siRNA, however, suppresses NSMase message, ∆Ψ loss, and apoptosis. The iPLA2β gene contains a sterol regulatory element (SRE) and transfection with a dominant negative SREBP-1 reduces basal mSREBP-1 and iPLA2β in the Akita cells and suppresses increases in mSREBP-1 and iPLA2β due to thapsigargin. These findings suggest that ER stress leads to generation of mSREBP-1, which can bind to the SRE in the iPLA2β gene to promote its transcription. Consistent with this, SREBP-1, iPLA2β, and NSMase messages in Akita Mouse islets are higher than in WT islets.

  • Spontaneous Development of Endoplasmic Reticulum Stress That Can Lead to Diabetes Mellitus Is Associated with Higher Calcium-independent Phospholipase A2 Expression: A ROLE FOR REGULATION BY SREBP-1*
    The Journal of biological chemistry, 2009
    Co-Authors: Xiaoyong Lei, Akio Koizumi, Sheng Zhang, Suzanne E. Barbour, Alan Bohrer, Eric L. Ford, Feroz R. Papa, Sasanka Ramanadham
    Abstract:

    Our recent studies indicate that endoplasmic retireticulum (ER) stress causes INS-1 cell apoptosis by a Ca2+-independent phospholipase A2 (iPLA2β)-mediated mechanism that promotes ceramide generation via sphingomyelin hydrolysis and subsequent activation of the intrinsic pathway. To elucidate the association between iPLA2β and ER stress, we compared β-cell lines generated from wild type (WT) and Akita mice. The Akita Mouse is a spontaneous model of ER stress that develops hyperglycemia/diabetes due to ER stress-induced β-cell apoptosis. Consistent with a predisposition to developing ER stress, basal phosphorylated PERK and activated caspase-3 are higher in the Akita cells than WT cells. Interestingly, basal iPLA2β, mature SREBP-1 (mSREBP-1), phosphorylated Akt, and neutral sphingomyelinase (NSMase) are higher, relative abundances of sphingomyelins are lower, and mitochondrial membrane potential (ΔΨ) is compromised in Akita cells, in comparison with WT cells. Exposure to thapsigargin accelerates ΔΨ loss and apoptosis of Akita cells and is associated with increases in iPLA2β, mSREBP-1, and NSMase in both WT and Akita cells. Transfection of Akita cells with iPLA2β small interfering RNA, however, suppresses NSMase message, ΔΨ loss, and apoptosis. The iPLA2β gene contains a sterol-regulatory element, and transfection with a dominant negative SREBP-1 reduces basal mSREBP-1 and iPLA2β in the Akita cells and suppresses increases in mSREBP-1 and iPLA2β due to thapsigargin. These findings suggest that ER stress leads to generation of mSREBP-1, which can bind to the sterol-regulatory element in the iPLA2β gene to promote its transcription. Consistent with this, SREBP-1, iPLA2β, and NSMase messages in Akita Mouse islets are higher than in WT islets.

  • Proinsulin lacking the A7-B7 disulfide bond, Ins2Akita, tends to aggregate due to the exposed hydrophobic surface.
    Biological Chemistry, 2005
    Co-Authors: Takeo Yoshinaga, Keisuke Nakatome, Jun-ichi Nozaki, Motoko Naitoh, Jun Hoseki, Hiroshi Kubota, Kazuhiro Nagata, Akio Koizumi
    Abstract:

    A single mutation (C96Y) in the Ins2 gene, which disrupts the A7-B7 disulfide bond, causes the diabetic phenotype in Akita mice. We biochemically analyzed the conformation of wild-type and Akita mutant recombinant proinsulins. Gel filtfiltration chromatography and dynamic light scattering revealed that the apparent size of the mutant proinsulin molecules was significantly larger than that of wild-type proinsulin, even in the absence of intermolecular disulfide bonds. Titration with a hydrophobic probe, 1 -anilinonaphthalene-8-sulfonate, demonstrated that the mutant proinsulin was more hydrophobic than the wild type. In addition, circular dichdichroism studies revealed that the conformation of the mutant proinsulin was less stable than the wild type, which is consistent with the observation that hydrophobic residues are exposed on the surface of the proinsulin molecules. Studies with antiserum against the C-peptpeptide of proinsulin indicated that the mutant proinsulin had an immunoreactivity that was at least one-tenth weaker than wild-type proinsulin, suggesting that the C-peptpeptide of mutant proinsulin is buried inside the aggregate of the proinsulin molecule. These findings indicate that increased hydrophobicity of mutant proinsulin facilitates aggregate formation, providing a clue to the dominant negative effect in the Akita Mouse.

Shaaban Abdo – One of the best experts on this subject based on the ideXlab platform.

  • overexpression of heterogeneous nuclear ribonucleoprotein f stimulates renal ace 2 gene expression and prevents tgf β1 induced kidney injury in a Mouse model of diabetes
    Diabetologia, 2015
    Co-Authors: Chaosheng Lo, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Shiaoying Chang, John S. D. Chan
    Abstract:

    Aims/hypothesis We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita Mouse model of type 1 diabetes.

  • Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a Mouse model of diabetes
    Diabetologia, 2015
    Co-Authors: Yixuan Shi, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Shiaoying Chang, John S. D. Chan
    Abstract:

    Aims/hypothesis We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita Mouse model of type 1 diabetes.

  • angiotensin 1 7 prevents systemic hypertension attenuates oxidative stress and tubulointerstitial fibrosis and normalizes renal angiotensin converting enzyme 2 and mas receptor expression in diabetic mice
    Clinical Science, 2015
    Co-Authors: Chaosheng Lo, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Ranjit Singh Padda, John S. D. Chan
    Abstract:

    We investigated the relationship between Ang-(1–7) [angiotensin-(1–7)] action, sHTN (systolic hypertension), oxidative stress, kidney injury, ACE2 (angiotensin-converting enzyme-2) and MasR [Ang-(1–7) receptor] expression in Type 1 diabetic Akita mice. Ang-(1–7) was administered daily [500 μg/kg of BW (body weight) per day, subcutaneously] to male Akita mice from 14 weeks of age with or without co-administration of an antagonist of the MasR, A779 (10 mg/kg of BW per day). The animals were killed at 20 weeks of age. Age-matched WT (wild-type) mice served as controls. Ang-(1–7) administration prevented sHTN and attenuated kidney injury (reduced urinary albumin/creatinine ratio, glomerular hyperfiltration, renal hypertrophy and fibrosis, and tubular apoptosis) without affecting blood glucose levels in Akita mice. Ang-(1–7) also attenuated renal oxidative stress and the expression of oxidative stress-inducible proteins (NADPH oxidase 4, nuclear factor erythroid 2-related factor 2, haem oxygenase 1), pro-hypertensive proteins (angiotensinogen, angiotensin-converting enzyme, sodium/hydrogen exchanger 3) and profibrotic proteins (transforming growth factor-β1 and collagen IV), and increased the expression of anti-hypertensive proteins (ACE2 and MasR) in Akita Mouse kidneys. These effects were reversed by A779. Our data suggest that Ang-(1–7) plays a protective role in sHTN and RPTC (renal proximal tubular cell) injury in diabetes, at least in part, through decreasing renal oxidative stress-mediated signalling and normalizing ACE2 and MasR expression.

Shao-ling Zhang – One of the best experts on this subject based on the ideXlab platform.

  • overexpression of heterogeneous nuclear ribonucleoprotein f stimulates renal ace 2 gene expression and prevents tgf β1 induced kidney injury in a Mouse model of diabetes
    Diabetologia, 2015
    Co-Authors: Chaosheng Lo, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Shiaoying Chang, John S. D. Chan
    Abstract:

    Aims/hypothesis We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita Mouse model of type 1 diabetes.

  • Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a Mouse model of diabetes
    Diabetologia, 2015
    Co-Authors: Yixuan Shi, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Shiaoying Chang, John S. D. Chan
    Abstract:

    Aims/hypothesis We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita Mouse model of type 1 diabetes.

  • angiotensin 1 7 prevents systemic hypertension attenuates oxidative stress and tubulointerstitial fibrosis and normalizes renal angiotensin converting enzyme 2 and mas receptor expression in diabetic mice
    Clinical Science, 2015
    Co-Authors: Chaosheng Lo, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Ranjit Singh Padda, John S. D. Chan
    Abstract:

    We investigated the relationship between Ang-(1–7) [angiotensin-(1–7)] action, sHTN (systolic hypertension), oxidative stress, kidney injury, ACE2 (angiotensin-converting enzyme-2) and MasR [Ang-(1–7) receptor] expression in Type 1 diabetic Akita mice. Ang-(1–7) was administered daily [500 μg/kg of BW (body weight) per day, subcutaneously] to male Akita mice from 14 weeks of age with or without co-administration of an antagonist of the MasR, A779 (10 mg/kg of BW per day). The animals were killed at 20 weeks of age. Age-matched WT (wild-type) mice served as controls. Ang-(1–7) administration prevented sHTN and attenuated kidney injury (reduced urinary albumin/creatinine ratio, glomerular hyperfiltration, renal hypertrophy and fibrosis, and tubular apoptosis) without affecting blood glucose levels in Akita mice. Ang-(1–7) also attenuated renal oxidative stress and the expression of oxidative stress-inducible proteins (NADPH oxidase 4, nuclear factor erythroid 2-related factor 2, haem oxygenase 1), pro-hypertensive proteins (angiotensinogen, angiotensin-converting enzyme, sodium/hydrogen exchanger 3) and profibrotic proteins (transforming growth factor-β1 and collagen IV), and increased the expression of anti-hypertensive proteins (ACE2 and MasR) in Akita Mouse kidneys. These effects were reversed by A779. Our data suggest that Ang-(1–7) plays a protective role in sHTN and RPTC (renal proximal tubular cell) injury in diabetes, at least in part, through decreasing renal oxidative stress-mediated signalling and normalizing ACE2 and MasR expression.

Isabelle Chenier – One of the best experts on this subject based on the ideXlab platform.

  • overexpression of heterogeneous nuclear ribonucleoprotein f stimulates renal ace 2 gene expression and prevents tgf β1 induced kidney injury in a Mouse model of diabetes
    Diabetologia, 2015
    Co-Authors: Chaosheng Lo, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Shiaoying Chang, John S. D. Chan
    Abstract:

    Aims/hypothesis We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita Mouse model of type 1 diabetes.

  • Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a Mouse model of diabetes
    Diabetologia, 2015
    Co-Authors: Yixuan Shi, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Shiaoying Chang, John S. D. Chan
    Abstract:

    Aims/hypothesis We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita Mouse model of type 1 diabetes.

  • angiotensin 1 7 prevents systemic hypertension attenuates oxidative stress and tubulointerstitial fibrosis and normalizes renal angiotensin converting enzyme 2 and mas receptor expression in diabetic mice
    Clinical Science, 2015
    Co-Authors: Chaosheng Lo, Shaaban Abdo, Isabelle Chenier, János G. Filep, Julie R. Ingelfinger, Shao-ling Zhang, Ranjit Singh Padda, John S. D. Chan
    Abstract:

    We investigated the relationship between Ang-(1–7) [angiotensin-(1–7)] action, sHTN (systolic hypertension), oxidative stress, kidney injury, ACE2 (angiotensin-converting enzyme-2) and MasR [Ang-(1–7) receptor] expression in Type 1 diabetic Akita mice. Ang-(1–7) was administered daily [500 μg/kg of BW (body weight) per day, subcutaneously] to male Akita mice from 14 weeks of age with or without co-administration of an antagonist of the MasR, A779 (10 mg/kg of BW per day). The animals were killed at 20 weeks of age. Age-matched WT (wild-type) mice served as controls. Ang-(1–7) administration prevented sHTN and attenuated kidney injury (reduced urinary albumin/creatinine ratio, glomerular hyperfiltration, renal hypertrophy and fibrosis, and tubular apoptosis) without affecting blood glucose levels in Akita mice. Ang-(1–7) also attenuated renal oxidative stress and the expression of oxidative stress-inducible proteins (NADPH oxidase 4, nuclear factor erythroid 2-related factor 2, haem oxygenase 1), pro-hypertensive proteins (angiotensinogen, angiotensin-converting enzyme, sodium/hydrogen exchanger 3) and profibrotic proteins (transforming growth factor-β1 and collagen IV), and increased the expression of anti-hypertensive proteins (ACE2 and MasR) in Akita Mouse kidneys. These effects were reversed by A779. Our data suggest that Ang-(1–7) plays a protective role in sHTN and RPTC (renal proximal tubular cell) injury in diabetes, at least in part, through decreasing renal oxidative stress-mediated signalling and normalizing ACE2 and MasR expression.