Mesangial cell protein kinase C isozyme activation in the diabetic milieu.
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-alpha, -beta, -delta, -epsilon, and -zeta 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-beta appears to be the key isozyme required for the enhanced expression of transforming growth factor-beta(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-beta, -delta, -epsilon and -zeta. Loss of mesangial cell contractility to potent vasoactive peptides and coincident F-actin disassembly are due to high-glucose-activation of PKC-zeta. Inhibition of mesangial cell PKC isozyme activation in high glucose may prove to be the next important treatment for diabetic nephropathy.
Whiteside
Catharine I
CI
University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8. catharine.whiteside@utoronto.ca
Dlugosz
John A
JA
D000818:Animals; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000201:enzymology*; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology; D004789:Enzyme Activation; D005920:Glomerular Mesangium / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*
D007527:Isoenzymes; D011493:Protein Kinase C