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Clinical and experimental evidence for oxidative stress as an exacerbating factor of diabetes mellitus.

Takayanagi R, Inoguchi T, Ohnaka K - J Clin Biochem Nutr (2010)

Bottom Line: Cross-sectional study of the Fukuoka Cohort revealed an inverse relation between serum bilirubin level and the prevalence of type 2 diabetes mellitus.These effects were paralleled with normalization of oxidative stress markers and expression of NAD(P)H oxidase subunits in kidney.These results suggested that oxidative stress is an exacerbating factor of type 2 diabetes mellitus and that antioxidant therapies are of value to diabetic nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

ABSTRACT
The involvement of reactive oxygen species in various diseases has been demonstrated almost in vitro or in animal studies and clinical studies supporting the involvement of reactive oxygen species are very few. Bilirubin has been recognized as an important antioxidant and also shown to have an inhibitory effect on the activity of NADPH oxidase, which may be an important source for superoxide production in various tissues. When the prevalence of vascular complcations was compared in diabetic patients with and without a congenital hyperbilirubinemia (Gilbert syndrome), the prevalence of retinopathy, macroalbuminuria and coronary artery disease in patients with Gilbert syndrome was about 20% of that in those without Gilbert syndrome. For study of lifestyle-related diseases, the Fukuoka Cohort was constructed from 2003 to 2009 in Kyushu area in Japan, which contains a total of 12,949 persons. Cross-sectional study of the Fukuoka Cohort revealed an inverse relation between serum bilirubin level and the prevalence of type 2 diabetes mellitus. A precursor of bilirubin, biliverdin-treated db/db mice exhibited less albuminuria and nephropathic changes. These effects were paralleled with normalization of oxidative stress markers and expression of NAD(P)H oxidase subunits in kidney. These results suggested that oxidative stress is an exacerbating factor of type 2 diabetes mellitus and that antioxidant therapies are of value to diabetic nephropathy.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of NOX4 protein levels in renal tissues of Gunn rats A and db mice B. NOX4 levels were normalized to the level of β-actin, and the results are expressed as the mean percentages of the levels in non-treated control rats. Results are expressed as means ± SE. **: p<0.01, ***: p<0.001. Reproduced from (23) with permission.
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Figure 5: Western blot analysis of NOX4 protein levels in renal tissues of Gunn rats A and db mice B. NOX4 levels were normalized to the level of β-actin, and the results are expressed as the mean percentages of the levels in non-treated control rats. Results are expressed as means ± SE. **: p<0.01, ***: p<0.001. Reproduced from (23) with permission.

Mentions: Hereditary hyperbilirubinemic homologous Gunn j/j rats and age-matched control heterozygous Gunn rats j/+ rats were induced to diabetes by intraperitoneal injection of streptozotocin. At 8 weeks after the onset of diabetes, the total serum bilirubin levels were 0.15 ± 0.02 and 0.18 ± 0.04 mg/dl in diabetic and non-diabetic Gunn j/+ rats, respectively, and 7.01 ± 0.43 and 9.47 ± 0.04 mg/dl in diabetic and non-diabetic Gunn j/j rats, respectively. Diabetic Gunn j/+ rats exhibited marked increases in the amounts of urinary albumin excretion compared with non-diabetic Gunn j/+ rats at 8 weeks after the onset of diabetes, whereas diabetic Gunn j/j rats exhibited significantly less urinary albumin excretion than diabetic Gunn j/+ rats (Fig. 3). Urinary excretion levels of a systemic oxidative stress marker, 8-hydroxy-2'-deoxyguanosine (8-OHdG), were significantly higher in diabetic Gunn j/+ rats than in non-diabetic Gunn j/+ rats at 8 weeks. The diabetes-induced increases in 8-OHdG at 8 weeks were completely prevented in diabetic hyperbilirubinemic Gunn j/j rats (Fig. 4A). Immunostaining analysis of 8-OHdG in renal tissues revealed that the staining intensities in diabetic Gunn j/+ rats were significantly higher than those in control Gunn j/+ rats, in both glomeruli and tubules at 24 weeks. These increases in 8-OHdG staining intensities in glomeruli and tubules were completely prevented in diabetic Gunn j/j rats. Furthermore, we examined the expression of renal NOX components by immunostaining analysis. The staining intensities for NOX4 protein were stronger in the renal glomeruli and tubules of diabetic Gunn j/+ rats than in those of control Gunn j/+ rats. Western blotting analysis confirmed that the protein levels for NOX4 were significantly increased in the kidneys of diabetic Gunn j/+ rats compared with control Gunn j/+ rats. All of these changes were completely prevented in diabetic Gunn j/j rats, which showed levels comparable to those in control Gunn j/+ rats (Fig. 5A). We investigated the effect of hyperbilirubinemia on mesangial expansion at 24 weeks after the onset of diabetes. The glomerular structure in diabetic Gunn j/+ rats showed accelerated mesangial expansion compared with that observed in control Gunn j/+ rats. The PAS-positive and nuclei-free mesangial area was markedly increased in the glomeruli of diabetic Gunn j/+ rats. Diabetic Gunn j/j rats showed complete prevention of mesangial expansion.


Clinical and experimental evidence for oxidative stress as an exacerbating factor of diabetes mellitus.

Takayanagi R, Inoguchi T, Ohnaka K - J Clin Biochem Nutr (2010)

Western blot analysis of NOX4 protein levels in renal tissues of Gunn rats A and db mice B. NOX4 levels were normalized to the level of β-actin, and the results are expressed as the mean percentages of the levels in non-treated control rats. Results are expressed as means ± SE. **: p<0.01, ***: p<0.001. Reproduced from (23) with permission.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3022068&req=5

Figure 5: Western blot analysis of NOX4 protein levels in renal tissues of Gunn rats A and db mice B. NOX4 levels were normalized to the level of β-actin, and the results are expressed as the mean percentages of the levels in non-treated control rats. Results are expressed as means ± SE. **: p<0.01, ***: p<0.001. Reproduced from (23) with permission.
Mentions: Hereditary hyperbilirubinemic homologous Gunn j/j rats and age-matched control heterozygous Gunn rats j/+ rats were induced to diabetes by intraperitoneal injection of streptozotocin. At 8 weeks after the onset of diabetes, the total serum bilirubin levels were 0.15 ± 0.02 and 0.18 ± 0.04 mg/dl in diabetic and non-diabetic Gunn j/+ rats, respectively, and 7.01 ± 0.43 and 9.47 ± 0.04 mg/dl in diabetic and non-diabetic Gunn j/j rats, respectively. Diabetic Gunn j/+ rats exhibited marked increases in the amounts of urinary albumin excretion compared with non-diabetic Gunn j/+ rats at 8 weeks after the onset of diabetes, whereas diabetic Gunn j/j rats exhibited significantly less urinary albumin excretion than diabetic Gunn j/+ rats (Fig. 3). Urinary excretion levels of a systemic oxidative stress marker, 8-hydroxy-2'-deoxyguanosine (8-OHdG), were significantly higher in diabetic Gunn j/+ rats than in non-diabetic Gunn j/+ rats at 8 weeks. The diabetes-induced increases in 8-OHdG at 8 weeks were completely prevented in diabetic hyperbilirubinemic Gunn j/j rats (Fig. 4A). Immunostaining analysis of 8-OHdG in renal tissues revealed that the staining intensities in diabetic Gunn j/+ rats were significantly higher than those in control Gunn j/+ rats, in both glomeruli and tubules at 24 weeks. These increases in 8-OHdG staining intensities in glomeruli and tubules were completely prevented in diabetic Gunn j/j rats. Furthermore, we examined the expression of renal NOX components by immunostaining analysis. The staining intensities for NOX4 protein were stronger in the renal glomeruli and tubules of diabetic Gunn j/+ rats than in those of control Gunn j/+ rats. Western blotting analysis confirmed that the protein levels for NOX4 were significantly increased in the kidneys of diabetic Gunn j/+ rats compared with control Gunn j/+ rats. All of these changes were completely prevented in diabetic Gunn j/j rats, which showed levels comparable to those in control Gunn j/+ rats (Fig. 5A). We investigated the effect of hyperbilirubinemia on mesangial expansion at 24 weeks after the onset of diabetes. The glomerular structure in diabetic Gunn j/+ rats showed accelerated mesangial expansion compared with that observed in control Gunn j/+ rats. The PAS-positive and nuclei-free mesangial area was markedly increased in the glomeruli of diabetic Gunn j/+ rats. Diabetic Gunn j/j rats showed complete prevention of mesangial expansion.

Bottom Line: Cross-sectional study of the Fukuoka Cohort revealed an inverse relation between serum bilirubin level and the prevalence of type 2 diabetes mellitus.These effects were paralleled with normalization of oxidative stress markers and expression of NAD(P)H oxidase subunits in kidney.These results suggested that oxidative stress is an exacerbating factor of type 2 diabetes mellitus and that antioxidant therapies are of value to diabetic nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

ABSTRACT
The involvement of reactive oxygen species in various diseases has been demonstrated almost in vitro or in animal studies and clinical studies supporting the involvement of reactive oxygen species are very few. Bilirubin has been recognized as an important antioxidant and also shown to have an inhibitory effect on the activity of NADPH oxidase, which may be an important source for superoxide production in various tissues. When the prevalence of vascular complcations was compared in diabetic patients with and without a congenital hyperbilirubinemia (Gilbert syndrome), the prevalence of retinopathy, macroalbuminuria and coronary artery disease in patients with Gilbert syndrome was about 20% of that in those without Gilbert syndrome. For study of lifestyle-related diseases, the Fukuoka Cohort was constructed from 2003 to 2009 in Kyushu area in Japan, which contains a total of 12,949 persons. Cross-sectional study of the Fukuoka Cohort revealed an inverse relation between serum bilirubin level and the prevalence of type 2 diabetes mellitus. A precursor of bilirubin, biliverdin-treated db/db mice exhibited less albuminuria and nephropathic changes. These effects were paralleled with normalization of oxidative stress markers and expression of NAD(P)H oxidase subunits in kidney. These results suggested that oxidative stress is an exacerbating factor of type 2 diabetes mellitus and that antioxidant therapies are of value to diabetic nephropathy.

No MeSH data available.


Related in: MedlinePlus