Abnormalities of retinal metabolism in diabetes or experimental galactosemia: V. Relationship between protein kinase C and ATPases.
In the retinas of diabetic animals, protein kinase C (PKC) activity is elevated, and Na+-K+-ATPase and calcium ATPase activities are subnormal. These abnormalities are also present in another model of diabetic retinopathy, experimental galactosemia. We have investigated the relationship between hyperglycemia-induced abnormalities of PKC and ATPases using a selective inhibitor of beta isoform of PKC (LY333531). Diabetes or experimental galactosemia of 2 months' duration resulted in > 50% elevation of PKC activity in the retina, and administration of LY333531 prevented the elevation. In retinas of the same rats, the LY333531 prevented hyperglycemia-induced decreases of both Na+-K+-ATPase and calcium ATPase activities. Retinal microvessels, the main site of lesions in diabetic retinopathy, likewise showed elevated activity of PKC and inhibition of ATPases in diabetes and in experimental galactosemia, and administration of LY333531 to diabetic animals prevented these abnormalities. PKC activity in sciatic nerves, in contrast, became subnormal in diabetes and experimental galactosemia, and LY333531 had no effect on PKC activity in the sciatic nerve. PKC activity in the cerebral cortex was not affected by diabetes or experimental galactosemia. The results suggest that diabetes-induced reductions in Na+-K+-ATPase and calcium ATPase in the retina are mediated in large part by PKC-beta. The availability of an agent that can normalize the hyperglycemia-induced increase in PKC activity in the retina should facilitate investigation of the role of PKC in the development of diabetic retinopathy.
Kowluru
R A
RA
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison 53706-1532, USA. rkowluru@facstaff.wisc.edu
Jirousek
M R
MR
Stramm
L
L
Farid
N
N
Engerman
R L
RL
Kern
T S
TS
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D015331:Cohort Studies; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology; D005693:Galactosemias / Q000139:chemically induced / Q000201:enzymology*; D007211:Indoles / Q000097:blood / Q000494:pharmacology; D008301:Maleimides / Q000097:blood / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000201:enzymology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase