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

Abstract

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.

Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice

“…These results therefore suggest that BNP exerts renoprotective effects in diabetes at least partly by locally inhibiting activation of the PKC-ERK pathway at the mesangium. The pathogenic role of PKC in matrix gene activation, haemodynamic abnormalities and proteinuria in vivo has already been shown in diabetic rodent models using a PKC β inhibitor [38,39].…”

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

“…In keeping with our findings, Hsieh et al reported recently that glucose-induced damage to proximal tubule cells is dependent on PKC-βI [14]. In addition, although there are conflicting results on which isoform(s) is(are) increased in the glomeruli of STZ-diabetic animals, with reports of increased levels of PKC-α [2, 10, 39], -βI [2,39,40], -δ [41] and -ɛ [10,41], PKC-βI seems to be the pathophysiological isoform [40,42]. Indeed, there is strong evidence that diabetes-induced mesangial cell damage occurs as a result of increased glucose uptake by GLUT1, which correlates with increased PKC-βI activation and fibronectin and collagen accumulation [1].…”

“…Levels of the extracellular matrix proteins collagen and fibronectin, as well as those of the profibrotic cytokine TGF-β are decreased in PKC-β −/− mice; moreover, a significant reduction in renal hypertrophy and glomerular enlargement is seen when PKC-β −/− mice are made diabetic and compared with wild-type mice [39,43]. Feeding of LY333531 to animals with STZ-induced diabetes has also been shown to prevent the increases in extracellular matrix components like fibronectin and collagen [2] and to reduce albuminuria and structural injury to the glomerulus [40,42,44]. Interestingly, inhibition of PKC-β by LY333531 also attenuated the diabetes-induced changes in the tubulointerstitium [40,45].…”

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

“…The PKC family of serine/threonine kinases consists of at least 12 isozymes that are classified into (1) conventional PKC␣, -␤ I and II , -␥ that depend on Ca 2ϩ and DAG or phorbol ester for activation; (2) novel PKC␦, -⑀, -, and -that are Ca 2ϩ independent but DAG or phorbol ester sensitive; and (3) atypical PKC , -, and -that require neither Ca 2ϩ nor phospholipids. The most intensively studied PKC isozyme in diabetes is the ␤ isozyme, and its specific inhibition by LY333531 prevents diabetic nephropathy both in STZ-induced Sprague-Dawley (SD) rat diabetes (30) and in db/db mice (31). Roles for other PKC isozymes in diabetes, particularly ␦ and isozymes, also have become of interest (32).…”