Normalization of Na(+)-K(+)-ATPase activity in isolated membrane fraction from sciatic nerves of streptozocin-induced diabetic rats by dietary myo-inositol supplementation in vivo or protein kinase C agonists in vitro.
A myo-inositol-related defect in nerve Na(+)-K(+)-ATPase in experimental diabetes has been invoked in the pathogenesis of diabetic neuropathy, but the mechanism linking altered myo-inositol metabolism and Na(+)-K(+)-ATPase regulation in diabetic nerve is uncertain. Decreased Na(+)-K(+)-ATPase in diabetic rat nerve is normalized by aldose reductase inhibitors or dietary myo-inositol, which preserve normal nerve myo-inositol content in vivo. Decreased Na(+)-K(+)-ATPase in diabetic rabbit nerve is acutely reversed by exposure to protein kinase C agonists in vitro. This study explored the relationship between the myo-inositol-sensitive and protein kinase C-agonist-sensitive Na(+)-K(+)-ATPase defects in diabetic rat nerve. Ouabain-sensitive ATPase activity was measured in an enriched membrane fraction isolated from nondiabetic, streptozocin-induced diabetic, and myo-inositol-supplemented streptozocin-induced diabetic rats before and after the membranes were exposed to protein kinase C agonists in vitro. The decreased ouabain-sensitive ATPase activity in plasma membranes from untreated diabetic rats was increased after exposure to two structurally unrelated protein kinase C agonists; the normal ouabain-sensitive ATPase in plasma membranes from myo-inositol-supplemented diabetic rats was unaffected by protein kinase C agonists. The nonadditivity and implied equivalence of the Na(+)-K(+)-ATPase defect corrected by myo-inositol in vivo and by protein kinase C agonists in vitro are consistent with the postulated existence of a deficient myo-inositol-dependent phospholipid-derived protein kinase C agonist (presumably diacylglycerol) in diabetic nerve that regulates nerve Na(+)-K(+)-ATPase either directly or via a protein kinase C mechanism.
Kim
J
J
Department of Biochemistry, University of Pittsburgh School of Medicine, Pennsylvania.
Kyriazi
H
H
Greene
D A
DA
D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004032:Diet; D004075:Diglycerides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007294:Inositol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012584:Sciatic Nerve / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D004075:Diglycerides; D007294:Inositol; D010042:Ouabain; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D013755:Tetradecanoylphorbol Acetate