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University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8
High-glucose-induced activation of
mesangial cell protein kinase C (PKC) contributes significantly to the
pathogenesis of diabetic nephropathy. Excess glucose metabolism through
the polyol pathway leads to de novo synthesis of both diacylglyerol
(DAG) and phosphatidic acid, which may account for increased mesangial cell PKC-
, -
, -
, -
, and -
activation/translocation
observed within 48-h exposure to high glucose. Raised intracellular
glucose causes generation of reactive oxygen species that may directly activate PKC isozymes and enhance their reactivity to vasoactive peptide signaling. In both diabetic rodent models of diabetes and
cultured mesangial cells, PKC- appears to be the key isozyme required for the enhanced expression of transforming growth
factor-1, initiation of early accumulation of mesangial
matrix protein, and increased microalbuminuria. Enhanced collagen IV
expression by mesangial cells in response to vasoactive peptide hormone
stimulation, e.g., endothelin-1, requires PKC-, -, - and -.
Loss of mesangial cell contractility to potent vasoactive peptides and
coincident F-actin disassembly are due to high-glucose-activation of
PKC-. Inhibition of mesangial cell PKC isozyme activation in high
glucose may prove to be the next important treatment for diabetic nephropathy.
diacylglycerol; polyol pathway; collagen IV; reactive oxygen species; endothelin-1
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