Ruboxistaurin is an inhibitor of the beta
isoform of
protein kinase C (
PKC-beta) that reduces the actions of
vascular endothelial growth factor (
VEGF) and attenuates the progression of
diabetic retinopathy. In the glomerulus
VEGF is constitutively expressed where it likely has a role in maintaining endothelial cell integrity, particularly in disease states. Given its potential use in
diabetic nephropathy, we sought to determine the effects of
PKC-beta inhibition on
VEGF and glomerular endothelial cells in experimental
diabetic nephropathy. Studies were conducted in (mRen-2)27 rat, a transgenic rodent with
hypertension and an enhanced renin-angiotensin system that following induction of diabetes with
streptozotocin develops many of the features of
diabetic nephropathy. Moreover, to mimic the clinical context, the effects of
PKC-beta inhibition were examined both with and without concomitant
angiotensin-converting enzyme (
ACE) inhibitor therapy. Diabetic Ren-2 rats were randomized to receive either vehicle, the
ACE inhibitor,
perindopril (0.2 mg/l in
drinking water),
ruboxistaurin (10 mg.kg(-1).day(-1), admixed in chow), or their combination and studied for 12 wk. Diabetic Ren-2 rats displayed glomerular endothelial cell loss in association with overexpression of
VEGF mRNA. Both cell loss and
VEGF overexpression were attenuated by the administration of either
perindopril or
ruboxistaurin, as single agent treatments with their combination providing additional, incremental improvements, reducing these manifestations of injury down to levels seen in nondiabetic, normotensive, nontransgenic animals. Combination
therapy was also associated with additional improvements in
albuminuria and glomerulosclerosis.