Protein kinase C β inhibition: the promise for treatment of diabetic nephropathy

  title={Protein kinase C $\beta$ inhibition: the promise for treatment of diabetic nephropathy},
  author={Pamela W. Anderson and Janet B. McGill and Katherine R. Tuttle},
  journal={Current Opinion in Nephrology and Hypertension},
Purpose of reviewThe prevalence of diabetes mellitus is increasing rapidly worldwide. The number of patients with diabetic nephropathy is also expected to increase considerably in the future despite currently available treatments that may prevent or slow kidney disease progression. Additional therapeutic agents are therefore urgently needed. Recent findingsRuboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the β-isoform of protein kinase C. In animal models of diabetic… 
Novel approaches targeted toward oxidative stress for the treatment of chronic kidney disease
It is believed that intercepting these pathways with one or more drugs may provide novel therapeutic modalities for halting progression of chronic kidney disease.
Renal and Vascular Mechanisms of Thiazolidinedione-Induced Fluid Retention
New evidence indicates that increased vascular permeability in adipose tissues may contribute to edema formation and body weight gain and future research should therefore be directed at achieving a better understanding of the detailed mechanisms of TZD-induced increases in renal sodium transport and in vascular permeable.
Akt and RhoA activation in response to high glucose require caveolin-1 phosphorylation in mesangial cells.
It is shown that, although the caveolin-1 protein level had no significant change, the PKC-β-specific inhibitor LY-333531 blocked cavelin-1 Y14 phosphorylation in high glucose (HG)-treated MCs and in the renal cortex of diabetic rats, and Caveolin- 1 is thus an important mediator of the profibrogenic process in diabetic renal disease.
PKCβ/NF-κB pathway in diabetic atrial remodeling.
Pharmacological inhibition of PKCβ is an effective method to reduce AF incidence in diabetic rat models by preventing NF-κB/TGF-β-mediated atrial remodeling.
High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation.
RhoA activation by glucose is dependent on PKC β1-induced ROS generation, most likely through NADPH oxidase, and the activation of PKCβ1 and its downstream effects, including upregulation of TGF-β1, requires caveolae.
PKC-beta1 mediates glucose-induced Akt activation and TGF-beta1 upregulation in mesangial cells.
In conclusion, PKC-beta1 is an Akt S473 kinase in glucose-treated mesangial cells, and TGF- beta1 transcriptional upregulation requires EGFR/PKC-beta2/Akt signaling, particularly the initial EGFR transactivation.
Therapeutic Drug Development for Kidney Diseases
This chapter will explore drug development across the spectrum of kidney disease. This ranges from acute kidney injury (AKI) to specific causes of chronic kidney disease (CKD) such as polycystic


Effect of ruboxistaurin on urinary transforming growth factor-beta in patients with diabetic nephropathy and type 2 diabetes.
Urine was obtained from participants in a prospective, double-blind, placebo-controlled study of the effects of ruboxistaurin 32 mg/day in patients with diabetic nephropathy, in which the effect on urinary TGF-β was a prespecified secondary objective.
Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension.
In vivo inhibition of PKC beta with LY333531 led to a reduction in albuminuria, structural injury, and TGF-beta expression, despite continued hypertension and hyperglycemia.
The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone.
The effect of ruboxistaurin on nephropathy in type 2 diabetes.
In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR over 1 year, and may add benefit to established therapies for diabetic neephropathy.
Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes, independent of the reduction in blood pressure it causes.
Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC β inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes
  • D. Koya, M. Haneda, R. Kikkawa
  • Biology, Medicine
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2000
These findings provide the first in vivo evidence that the long‐term inhibition of PKC activation in the renal glomeruli can ameliorate glomerular pathologies in diabetic state, and suggest that a PKC β inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
Deletion of Protein Kinase C-β Isoform In Vivo Reduces Renal Hypertrophy but Not Albuminuria in the Streptozotocin-Induced Diabetic Mouse Model
The differential effects of PKC-β deficiency on diabetes-induced renal hypertrophy and albuminuria suggest that PKC–β contributes to high-glucose–induced TGF-β1 expression and renal fibrosis, whereas perlecan, as well as nephrin, expression andalbuminuria is regulated by other signaling pathways.
Activation of Protein Kinase C in Glomerular Cells in Diabetes: Mechanisms and Potential Links to the Pathogenesis of Diabetic Glomerulopathy
Observations suggest that activation of the PKC system by hyperglycemia may represent an important pathway by which glucotoxicity is transduced in susceptible cells in diabetes.
Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC β Inhibitor
When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities.