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implicated in the decreased glomerular production of nitric oxide
induced by experimental diabetes
60
, and in the decreased production
of nitric oxide in smooth muscle cells that is induced by hypergly-
caemia
61
. Activation of PKC also inhibits insulin-stimulated 
expression of the messenger RNA for endothelial nitric oxide 
synthase (eNOS) in cultured endothelial cells
62
. Hyperglycaemia
increases endothelin-1-stimulated MAP-kinase activity in glomeru-
lar mesangial cells by activating PKC isoforms
63
. The increased 
permeability of endothelial cells induced by high glucose in cultured
cells is mediated by activation of PKC-
a, however
64
. Activation of
PKC by raised glucose also induces expression of the permeability-
enhancing factor VEGF in smooth muscle cells
65
.
In addition to affecting hyperglycaemia-induced abnormalities
of blood flow and permeability, activation of PKC contributes to
increased microvascular matrix protein accumulation by inducing
expression of TGF-
b1, fibronectin and type IV collagen both in cul-
tured mesangial cells
66
and in glomeruli of diabetic rats
67
. This effect
seems to be mediated through inhibition of nitric oxide production
by PKC
68
. But hyperglycaemia-induced expression of laminin C1 in
cultured mesangial cells is independent of PKC activation
69
. 
Hyperglycaemia-induced activation of PKC has also been implicated
in the overexpression of the fibrinolytic inhibitor PAI-1 (ref. 70), the
activation of NF-
kB in cultured endothelial cells and vascular
smooth muscle cells
71,72
, and in the regulation and activation of 
various membrane-associated NAD(P)H-dependent oxidases.
Treatment with an inhibitor specific for PKC-
b significantly
reduced PKC activity in the retina and renal glomeruli of diabetic 
animals. Concomitantly, treatment significantly reduced diabetes-
induced increases in retinal mean circulation time, normalized
increases in glomerular filtration rate and partially corrected urinary
albumin excretion. Treatment of a mouse model of type 2 diabetes
(db/db) with a 
b-isoform-specific PKC inhibitor ameliorated 
accelerated glomerular mesangial expansion
73
.

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