Abstract
This study characterizes the effect of glucose-induced activation of protein kinase Cδ (PKCδ) and Src homology-2 domain-containing phosphatase-1 (SHP-1) expression on vascular endothelial growth factor (VEGF) actions in glomerular podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose levels induced PKCδ and p38 mitogen-activated protein kinase (p38 MAPK) to increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerular endothelial cells. The adverse effects of high glucose levels can be negated by molecular inhibitors of PKCδ, p38MAPK, and SHP-1 and only partially reduced by antioxidants and nuclear factor-κB (NF-κB) inhibitor. Increased PKCδ activation and SHP-1 expression correlated with loss of VEGF signaling and podocyte numbers in the glomeruli of diabetic rats and mice. In contrast, diabetic PKCδ-knockout (Prkcd(-/-)) mice did not exhibit activation of p38 MAPK and SHP-1 or inhibition of VEGF signaling in renal glomeruli. Functionally, diabetic Prkcd(-/-) mice had decreased expressions of TGFβ, VEGF, and extracellular matrix and less albuminuria than diabetic Prkcd(+/+) mice. Hyperglycemia and diabetes can cause glomerular podocyte apoptosis and endothelial dysfunction partly due to increased PKCδ/p38 MAPK activation and the expression of SHP-1 to cause VEGF resistance, independent of NF-κB activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Base Sequence
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Cells, Cultured
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Diabetic Nephropathies / etiology*
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Diabetic Nephropathies / genetics
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Diabetic Nephropathies / metabolism*
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Diabetic Nephropathies / pathology
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Endothelial Cells / metabolism
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Enzyme Activation
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Female
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Glucose / metabolism
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Kidney Glomerulus / metabolism
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Male
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Mice
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Mice, Knockout
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NF-kappa B / metabolism
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Podocytes / metabolism
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Podocytes / pathology
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Protein Kinase C-delta / antagonists & inhibitors
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Protein Kinase C-delta / deficiency
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Protein Kinase C-delta / genetics
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Protein Kinase C-delta / metabolism*
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
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RNA, Small Interfering / genetics
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Rats
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Rats, Sprague-Dawley
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Signal Transduction
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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NF-kappa B
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RNA, Small Interfering
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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vascular endothelial growth factor A, rat
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Prkcd protein, mouse
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Prkcd protein, rat
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Vascular Endothelial Growth Factor Receptor-2
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Protein Kinase C-delta
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p38 Mitogen-Activated Protein Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Ptpn6 protein, mouse
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Ptpn6 protein, rat
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Glucose