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

Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan.
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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    ABSTRACT: Diabetic nephropathy (DN) is a secondary complication of both type 1 and type 2 diabetes, resulting from uncontrolled high blood sugar. 30-40 % of diabetic patients develop DN associated with a poor life expectancy and end-stage renal disease, causing serious socioeconomic problems. Although an exact pathogenesis of DN is still unknown, several factors such as hyperglycemia, hyperlipidemia, hypertension and proteinuria may contribute to the progression of renal damage in diabetic nephropathy. DN is confirmed by measuring blood urea nitrogen, serum creatinine, creatinine clearance and proteinuria. Clinical studies show that intensive control of hyperglycemia and blood pressure could successfully reduce proteinuria, which is the main sign of glomerular lesions in DN, and improve the renal prognosis in patients with DN. Diabetic rodent models have traditionally been used for doing research on pathogenesis and developing novel therapeutic strategies, but have limitations for translational research. Diabetes in animal models such as rodents are induced either spontaneously or by using chemical, surgical, genetic, or other techniques and depicts many clinical features or related phenotypes of the disease. This review discusses the merits and demerits of the models, which are used for many reasons in the research of diabetes and diabetic complications.
    Inflammopharmacology 08/2014; 22(5). DOI:10.1007/s10787-014-0215-y
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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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    ABSTRACT: Diabetic nephropathy (DN) is one of the microvascular complications of both type 1 and type 2 diabetes, which is also associated with a poor life expectancy of diabetic patients. However, the pathogenesis of DN is still unclear. Thus, it is of great use to establish appropriate animal models of DN for doing research on pathogenesis and developing novel therapeutic strategies. Although a large number of murine models of DN including artificially induced, spontaneous, and genetically engineered (knockout and transgenic) animal models have been developed, none of them develops renal changes sufficiently reflecting those seen in humans. Here we review the identified murine models of DN from the aspects of genetic background, type of diabetes, method of induction, gene deficiency, animal age and gender, kidney histopathology, and phenotypic alterations in the hope of enhancing our comprehension of genetic susceptibility and molecular mechanisms responsible for this disease and providing new clues as to how to choose appropriate animal models of DN.
    Journal of Diabetes Research 06/2013; 2013(6):797548. DOI:10.1155/2013/797548 · 2.16 Impact Factor
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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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    ABSTRACT: Diabetes Mellitus is one of the common metabolic disorders with micro and macro vascular complications that results in significant morbidity and mortality. The persistent hyperglycemia is responsible for the appearance of various organ and tissue damage in diabetic subjects. Eyes, kidneys and peripheral nerves are frequently damaged due to diabetes-specific alteration in microvessels. Furthermore, large vessels are also damaged causing severe diseases such as myocardial infarction, cerebral infarction and gangrene. The pathogenesis of these alterations in small and large vessels has been extensively studied and various metabolic abnormalities induced by hyperglycemia are proposed to play a major role in the development of these diabetic vascular complications. Among those metabolic abnormalities, the activation of the diacyl glycerol-protein kinase C pathway has been proposed to play a pivotal role in the pathogenesis of not only microvascular complications but also macrovascular complications. The results of several largescale clinical trials have confirmed the efficacy of glycemic control as well as blood pressure control in the management of diabetic complications. It is a prerequisite, therefore, to obtain near-normal glycemic and blood pressure control in order to prevent the appearance of diabetic complications and also suppress their progression. In this aspect nutritional consideration and herbal preparations may be an important way to improve the quality of these managements.
    International Journal of Research in Pharmacy and Chemistry 01/2013; 3(4).
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