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Updated: Jul 14, 2026
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Effects on protein kinase C-beta inhibition on glomerular vascular endothelial growth factor expression and
Darren J Kelly1, Danielle Buck, Alison J Cox
1Dept. of Medicine, St. Vincent's Hospital, Fitzroy, Victoria 3065, Australia. dkelly@medstv.unimelb.edu.au
Abstract:
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.
Insights
Ruboxistaurin, a protein kinase C-beta inhibitor, and ACE inhibitors like perindopril protect against diabetic nephropathy by reducing glomerular endothelial cell loss and vascular endothelial growth factor (VEGF) overexpression.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Diabetic nephropathy is characterized by glomerular endothelial cell damage and altered vascular endothelial growth factor (VEGF) expression.
- Protein kinase C-beta (PKC-beta) signaling and VEGF play critical roles in the pathogenesis of diabetic kidney disease.
- Ruboxistaurin, a selective PKC-beta inhibitor, has shown potential in treating microvascular complications of diabetes.
Purpose of the Study:
- To investigate the effects of PKC-beta inhibition on VEGF and glomerular endothelial cells in experimental diabetic nephropathy.
- To evaluate the efficacy of ruboxistaurin, alone and in combination with an angiotensin-converting enzyme (ACE) inhibitor, in a rat model of diabetic nephropathy.
Main Methods:
- Studies were conducted in (mRen-2)27 rats, a transgenic model of hypertension and enhanced renin-angiotensin system, induced with diabetes using streptozotocin.
- Diabetic rats were randomized to receive vehicle, perindopril (ACE inhibitor), ruboxistaurin (PKC-beta inhibitor), or combination therapy for 12 weeks.
- Glomerular endothelial cell count, VEGF mRNA expression, albuminuria, and glomerulosclerosis were assessed.
Main Results:
- Diabetic rats exhibited significant glomerular endothelial cell loss and overexpression of VEGF mRNA.
- Both perindopril and ruboxistaurin, as monotherapies, attenuated cell loss and VEGF overexpression.
- Combination therapy provided additional incremental improvements, reducing these markers to levels seen in non-diabetic animals, with further benefits in albuminuria and glomerulosclerosis.
Conclusions:
- PKC-beta inhibition with ruboxistaurin effectively mitigates key pathological features of experimental diabetic nephropathy.
- Combination therapy with an ACE inhibitor offers enhanced renoprotective effects beyond monotherapy.
- Targeting PKC-beta and the renin-angiotensin system represents a promising therapeutic strategy for diabetic kidney disease.
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