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.
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.
Koya
D
D
Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan.
Haneda
M
M
Nakagawa
H
H
Isshiki
K
K
Sato
H
H
Maeda
S
S
Sugimoto
T
T
Yasuda
H
H
Kashiwagi
A
A
Ways
D K
DK
King
G L
GL
Kikkawa
R
R
D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology*; D007211:Indoles / Q000627:therapeutic use*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000201:enzymology*; D008297:Male; D008301:Maleimides / Q000627:therapeutic use*; D051379:Mice; D008817:Mice, Mutant Strains; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D016212:Transforming Growth Factor beta / Q000235:genetics
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D016212:Transforming Growth Factor beta; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta