CHARACTERIZATION OF PROTEIN-KINASE-C BETA-ISOFORM ACTIVATION ON THE GENE-EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA, EXTRACELLULAR-MATRIX COMPONENTS, AND PROSTANOIDS IN THE GLOMERULI OF DIABETIC RATS
D. Koya et al., CHARACTERIZATION OF PROTEIN-KINASE-C BETA-ISOFORM ACTIVATION ON THE GENE-EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA, EXTRACELLULAR-MATRIX COMPONENTS, AND PROSTANOIDS IN THE GLOMERULI OF DIABETIC RATS, The Journal of clinical investigation, 100(1), 1997, pp. 115-126
Induction of protein kinase C (PKC) pathway in the vascular tissues by
hyperglycemia has been associated with many of the cellular changes o
bserved in the complications of diabetes. Recently, we have reported t
hat the use of a novel, orally effective specific inhibitor of PKC bet
a isoform (LY333531) normalized many of the early retinal and renal he
modynamics in rat models of diabetes, In the present study, we have ch
aracterized a spectrum of biochemical and molecular abnormalities asso
ciated with chronic changes induced by glucose or diabetes in the cult
ured mesangial cells and renal glomeruli that can be prevented by LY33
3531, Hyperglycemia increased diacylglycerol (DAG) level in cultured m
esangial cells exposed to high concentrations of glucose and activated
PKC alpha and beta 1 isoforms in the renal glomeruli of diabetic rats
. The addition of PKC beta selective inhibitor (LY333531) to cultured
mesangial cells inhibited activated PKC activities by high glucose wit
hout lowering DAG levels and LY333531 given orally in diabetic rats sp
ecifically inhibited the activation of PKC beta 1 isoform without decr
easing PKC alpha isoform activation, Glucose-induced increases in arac
hidonic acid release, prostaglandin E-2 production, and inhibition of
Na+-K+ ATPase activities in the cultured mesangial cells were complete
ly prevented by the addition of LY333531, Oral feeding of LY333531 pre
vented the increased mRNA expression of TGF-beta 1 and extracellular m
atrix components such as fibronectin and alpha 1(IV) collagen in the g
lomeruli of diabetic rats in parallel with inhibition of glomerular PK
C activity, These results suggest that the activation of PKC, predomin
ately the beta isoform by hyperglycemia in the mesangial cells and glo
meruli can partly contribute to early renal dysfunctions by alteration
of prostaglandin production and Na+-K+ ATPase activity as well as the
chronic pathological changes by the overexpression of TGF-beta 1 and
extracellular matrix components genes.