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* Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan;
Department of Pathology, Otowa Hospital, Yamashina, Kyoto 607-8062, Japan;
Lilly Research Laboratories, Indianapolis, Indianapolis 46285, USA; and
§ Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA
1Correspondence: Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan. E-mail: haneda{at}belle.shiga-med.ac.jp
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 ß 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 ß1 (TGF-ß1) 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 ß 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 ß inhibitor reduced urinary albumin excretion rates and inhibited glomerular PKC activation in diabetic db/db mice. Administration of a PKC ß inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of glomerular expression of TGF-ß 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 ß inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.—Koya, D., Haneda, M., Nakagawa, H., Isshiki, K., Sato, H., Maeda, S., Sugimoto, T., Yasuda, H., Kashiwagi, A., Ways, D. K., King, G. L., Kikkawa, R. Amelioration of accelerated diabetic mesangial expansion by treatment with A PKC ß inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes.
Key Words: transforming growth factor ß (TGF-ß) • fibronectin • type IV collagen • diabetic nephropathy
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