GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy

Charles W. Heilig, Dilip K. Deb, Afu Abdul, Hasan Riaz, Leighton R James, Jamal Salameh, Norris Stanley Nahman

Research output: Contribution to journalReview article

25 Citations (Scopus)

Abstract

Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

Original languageEnglish (US)
Pages (from-to)39-49
Number of pages11
JournalAmerican Journal of Nephrology
Volume38
Issue number1
DOIs
StatePublished - Apr 12 2013

Fingerprint

Diabetic Nephropathies
Glucose
Glycerol Kinase
Angiotensin II
Vascular Endothelial Growth Factor A
Connective Tissue Growth Factor
Intercellular Signaling Peptides and Proteins
Mesangial Cells
Transforming Growth Factors
Protein Kinase C
Somatomedin Receptors
Platelet-Derived Growth Factor Receptors
Growth Factor Receptors
Facilitative Glucose Transport Proteins
MAP Kinase Signaling System
Extracellular Matrix Proteins
Glycolysis
Growth and Development
Epidermal Growth Factor Receptor
Hyperglycemia

Keywords

  • Diabetic nephropathy
  • GLUT1
  • Glomerulosclerosis
  • Glucose transporter
  • Growth factors
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Nephrology

Cite this

GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy. / Heilig, Charles W.; Deb, Dilip K.; Abdul, Afu; Riaz, Hasan; James, Leighton R; Salameh, Jamal; Nahman, Norris Stanley.

In: American Journal of Nephrology, Vol. 38, No. 1, 12.04.2013, p. 39-49.

Research output: Contribution to journalReview article

Heilig, Charles W. ; Deb, Dilip K. ; Abdul, Afu ; Riaz, Hasan ; James, Leighton R ; Salameh, Jamal ; Nahman, Norris Stanley. / GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy. In: American Journal of Nephrology. 2013 ; Vol. 38, No. 1. pp. 39-49.
@article{7757975b3bc3405f8b90387e7ab4fe2b,
title = "GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy",
abstract = "Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.",
keywords = "Diabetic nephropathy, GLUT1, Glomerulosclerosis, Glucose transporter, Growth factors, Vascular endothelial growth factor",
author = "Heilig, {Charles W.} and Deb, {Dilip K.} and Afu Abdul and Hasan Riaz and James, {Leighton R} and Jamal Salameh and Nahman, {Norris Stanley}",
year = "2013",
month = "4",
day = "12",
doi = "10.1159/000351989",
language = "English (US)",
volume = "38",
pages = "39--49",
journal = "American Journal of Nephrology",
issn = "0250-8095",
publisher = "S. Karger AG",
number = "1",

}

TY - JOUR

T1 - GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy

AU - Heilig, Charles W.

AU - Deb, Dilip K.

AU - Abdul, Afu

AU - Riaz, Hasan

AU - James, Leighton R

AU - Salameh, Jamal

AU - Nahman, Norris Stanley

PY - 2013/4/12

Y1 - 2013/4/12

N2 - Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

AB - Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

KW - Diabetic nephropathy

KW - GLUT1

KW - Glomerulosclerosis

KW - Glucose transporter

KW - Growth factors

KW - Vascular endothelial growth factor

UR - http://www.scopus.com/inward/record.url?scp=84879493776&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879493776&partnerID=8YFLogxK

U2 - 10.1159/000351989

DO - 10.1159/000351989

M3 - Review article

C2 - 23817135

AN - SCOPUS:84879493776

VL - 38

SP - 39

EP - 49

JO - American Journal of Nephrology

JF - American Journal of Nephrology

SN - 0250-8095

IS - 1

ER -