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

Harvard University, Cambridge, Massachusetts, United States
The FASEB Journal (Impact Factor: 5.04). 04/2000; 14(3):439-47.
Source: PubMed


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.

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Available from: Daisuke Koya
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    • "After 16 weeks of age, there is a very consistent threefold increase in mesangial matrix expansion based on several independent studies (Sharma et al. 2003). However, the degree of albuminuria does not consistently increase with the duration of diabetes, as there are similar levels of albuminuria between 8 and 25 weeks (Koya et al. 2000; Cohen et al. 2001; Sharma et al. 2003). The severity of diabetes in db/db mice depends on the C57BL/6 background in the diabetic phenotype and is less severe than that in C57BLKS/J; as these mice age, plasma glucose seems to normalize (Koenig et al. 1976; Leiter et al. 1981; Meade et al. 1981; Leiter et al. 1987, 1989). "
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    • "Albuminuria can be detected as early as 3 to 4 weeks after the onset of hyperglycemia [3]. The level of albuminuria in the db/db male mouse is 68–600 μg/24 h [20, 34–37] which is only 4–21 μg/24 h [34, 37] in the age-matched heterozygous littermate. The db/db mice display an increase in glomerular size and mesangial matrix by 5-6 months of age [20]. "
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    • "We have recently found that the inhibition of protein kinase C is able to revent the accumulation of extracellular matrix proteins in renal glomeruli in spontaneously diabetic db/db mice. This effect of protein kinase C inhibition appears to be transforming growth factor-beta mediated, that is, increased transforming growth factor-beta, which is a potent prosclerotic cytokine, may be protein kinase Cdependent (Koya et al. 2000). Furthermore, hyperglycemia increases the nonenzymatic glycation reaction between glucose and free amino groups in proteins, and therefore disturbs the biological function of various proteins. "
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