Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes

FASEB J. 2000 Mar;14(3):439-47. doi: 10.1096/fasebj.14.3.439.


Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced glomerular dysfunction such as glomerular hyperfiltration and albuminuria, but also overexpression of glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. 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 thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / prevention & control
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / pathology*
  • Diabetic Nephropathies / pathology
  • Diabetic Nephropathies / prevention & control*
  • Enzyme Inhibitors / therapeutic use*
  • Gene Expression Regulation / drug effects
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / pathology*
  • Indoles / therapeutic use*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism*
  • Kidney Glomerulus / enzymology*
  • Male
  • Maleimides / therapeutic use*
  • Mice
  • Mice, Mutant Strains
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Protein Kinase C beta
  • Rats
  • Transforming Growth Factor beta / genetics


  • Blood Glucose
  • Enzyme Inhibitors
  • Indoles
  • Isoenzymes
  • Maleimides
  • Transforming Growth Factor beta
  • ruboxistaurin
  • Protein Kinase C
  • Protein Kinase C beta