AGEs induce oxidative stress and activate protein kinase C-beta(II) in neonatal mesangial cells

Increased activation of specific protein kinase C (PKC) isoforms and increased nonenzymatic glycation of intracellular and extracellular proteins [the accumulation of advanced glycation end products (AGEs)] are major mechanistic pathways implicated in the pathogenesis of diabetic complications. Bloc...

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Bibliographic Details
Published in:American journal of physiology. Renal physiology 2000-04, Vol.278 (4), p.F676-F683
Main Authors: Scivittaro, V, Ganz, M B, Weiss, M F
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn - metabolism
Biological Transport - drug effects
Cell Division - physiology
Cells, Cultured
Enzyme Activation - physiology
Glomerular Mesangium - cytology
Glomerular Mesangium - drug effects
Glomerular Mesangium - metabolism
Glycation End Products, Advanced - pharmacology
Intracellular Membranes - metabolism
Isoenzymes - metabolism
Oxidative Stress
Protein Kinase C - metabolism
Protein Kinase C beta
Rats
Rats, Sprague-Dawley
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Summary:Increased activation of specific protein kinase C (PKC) isoforms and increased nonenzymatic glycation of intracellular and extracellular proteins [the accumulation of advanced glycation end products (AGEs)] are major mechanistic pathways implicated in the pathogenesis of diabetic complications. Blocking PKC-beta(II) has been shown to decrease albuminuria in animal models of diabetes. To demonstrate a direct relationship between AGEs and the induction and translocation of PKC-beta(II), studies were carried out in rat neonatal mesangial cells, known to express PKC-beta(II) in association with rapid proliferation in post-natal development. Oxidative stress was studied by using the fluorescent probe dichlorfluorescein diacetate. Translocation of PKC-beta(II) was demonstrated by using immunofluorescence and Western blotting of fractionated mesangial cells. Induction of intracellular oxidative stress, increase in intracellular calcium, and cytosol to membrane PKC-beta(II) translocation (with no change in PKC-alpha) were demonstrated after exposure to AGE-rich proteins. These data support the hypothesis that AGEs cause mesangial oxidative stress and alterations in PKC-beta(II), changes that may ultimately contribute to phenotypic abnormalities associated with diabetic nephropathy.
ISSN:1931-857X
DOI:10.1152/ajprenal.2000.278.4.f676