Affiliations: Third Department of Medicine, Shiga University of Medical Science, Otsu 520‐21, Japan | Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA
Note: [] To whom correspondence should be addressed: George L. King, M.D., Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA. Tel.: 617 732 2622; Fax: 617 732 2637; E‐mail: [email protected].
Abstract: Since diabetes now accounts for 35% of all new cases of end‐stage renal disease in the United States, it is really important to prevent the onset of diabetic nephropathy. Activation of protein kinase C (PKC) is implicated to be one of the causal factors in the development of renal dysfunctions in diabetes. In this study, we have demonstrated that total diacylglycerol (DAG) contents and PKC activity in glomeruli were significantly increased in diabetic rats as compared to control rats, but intraperitoneal injection of d‐\alpha‐tocopherol prevented these biochemical abnormalities in parallel with normalization of glomerular dysfunction such as increased glomerular filtration rate (GFR) in diabetic rats. Albuminuria in diabetic rats was also significantly increased as compared to control rats, whereas d‐\alpha‐tocopherol treatment again ameriolated increased albuminuria in parallel with the inhibition of glomerular PKC activation by diabetes. Moreover, we have observed that the activity of DAG kinase, which metabolizes DAG to phosphatidic acid and acts as an attenuator for the DAG‐PKC pathway, was enchanced by d‐\alpha‐tocopherol treatment. These results suggest that the increase in the DAG‐PKC pathway might play an important role for the development of glomerular dysfunctions in diabetes and d‐\alpha‐tocopherol treatment could be helpful in diabetic nephropathy.
