Amelioration of accelerated diabetic mesangial expansion by treatment witha 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 mechanis m by which diabetes causes vascular complications. We have recently shown t hat a PKC beta inhibitor ameliorates not only early diabetes-induced glomer ular dysfunction such as glomerular hyperfiltration and albuminuria, but al so overexpression of glomerular mRNA for transforming growth factor beta 1 (TGF-beta 1) and extracellular matrix (ECM) proteins in streptozotocin-indu ced 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 we ll as on biochemical and functional abnormalities in glomeruli of db/db mic e, a model for type 2 diabetes. Administration of a PKC beta inhibitor redu ced urinary albumin excretion rates and inhibited glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also preven ted the mesangial expansion observed in diabetic db/db mice, possibly throu gh attenuation of glomerular expression of TGF-beta and ECM proteins such a s fibronectin and type TV collagen. These findings provide the first in viv o evidence that the long-term inhibition of PKC activation in the renal glo meruli can ameliorate glomerular pathologies in diabetic state, and thus su ggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.