ROLE OF DIABETES-INDUCED GLOMERULAR PKC-MAPK ACTIVATION ON DIABETIC GLOMERULOSCLEROSIS

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Diabetic nephropathy is the leading cause of end-stage renal disease in Western and Asian society. Hyperglycemia is the single most important risk factor for the development of diabetic nephropathy. We have previously shown that short-term treatment of PKC β inhibitor ameliorated early changes of glomerular dysfunction such as glomerular hyperfiltration and increased albunimuria, and normalized the increase in mRNA expression of TGF-β1 and extracellular matrix components in stereotozotocin-induced diabetic rats. Thus, we have been suggesting the pivotal role of glomerular PKC β activation in the development of diabetic kidney disease. However, it remains elusive whether the long-term treatment with PKC β inhibitor can prevent pathological changes in glomeruli of diabetic rats or whether PKC β inhibitor is also effective in animals with type 2 diabetes. In this study, we tested whether the long-term effect of PKC β inhibitor could affect diabetes-induced mesangial expansion in parallel with its effect on biochemical and functional parameters such as glomerular PKC activity and albuminuria in both alloxan-induced diabetic rats, a model for type 1 diabetes and db/db mice, a model for type 2 diabetes. Treatment with PKC β inhibitor reduced the elevated urinary albumin excretion in parallel with its inhibitory effects on glomerular PKC activation. PKC β inhibitor also ameliorated the mesangial expansion observed in the untreated diabetic animals without affected blood glucose levels, body weight, and blood pressure. These findings have provided the first in vivo evidence that long-term inhibition of PKC activation, especially its β isoform, in the renal glomeruli was able to prevent glomerular pathologies in diabetic state irrespective of adverse effect, and identified PKC β inhibitor as a useful therapeutic agent for diabetic nephropathy.