Diabetes Metab J.  2012 Aug;36(4):255-261. 10.4093/dmj.2012.36.4.255.

The Role of Oxidative Stress in the Pathogenesis of Diabetic Vascular Complications

• Sasaki S
• Inoguchi T

• KMID: 2174415
• DOI: http://doi.org/10.4093/dmj.2012.36.4.255

Abstract

Oxidative stress has been paid increasing attention to as an important causative factor for diabetic vascular complications. Among possible various sources, accumulating evidence has indicated that NAD(P)H oxidase may be the most important source for reactive oxygen species production in diabetic vascular tissues. The mechanisms underlying activation and up-regulation of NAD(P)H oxidase has been supposed to be mediated by high glucose-induced protein kinase C (PKC) activation. In this review article, activation of local renin-angiotensin II system induced by chymase activation is also shown to amplify such a PKC-dependent activation of NAD(P)H oxidase. Additionally, human evidence showing the beneficial effect of antioxidants on diabetic vascular complications. Bilirubin has been recognized as a strong endogenous antioxidant. Here markedly lower prevalence of vascular complications is shown in diabetic patients with Gilbert syndrome, a congenital hyperbilirubinemia, as well as reduced markers of oxidative stress and inflammation. Lastly, statin, angiotensin II receptor blocker, chymase inhibitor, bilirubin and biliverdin, PKC beta isoform inhibitor, and glucagon-like peptide-1 analog, are shown to serve as antioxidants and have some beneficial effect on diabetic vascular complications, via inhibiting PKC-NAD(P)H oxidase activation, supporting the notion that this mechanism may be an effective therapeutic target for preventing diabetic vascular complications.

Keyword

Angiotensin II; Bilirubin; Chymases; NADPH oxidase; Oxidative stress; Protein kinase C

MeSH Terms

Angiotensin II
Antioxidants
Bilirubin
Biliverdine
Chymases
Diabetic Angiopathies
Gilbert Disease
Glucagon-Like Peptide 1
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hyperbilirubinemia
Inflammation
NADPH Oxidase
Oxidative Stress
Oxidoreductases
Prevalence
Protein Kinase C
Reactive Oxygen Species
Receptors, Angiotensin
Up-Regulation
Angiotensin II
Antioxidants
Bilirubin
Biliverdine
Chymases
Glucagon-Like Peptide 1
Hydroxymethylglutaryl-CoA Reductase Inhibitors
NADPH Oxidase
Oxidoreductases
Protein Kinase C
Reactive Oxygen Species
Receptors, Angiotensin

Figure

• 

  Fig. 1 Serum high sensitivity C-reactive protein (hs-CRP) levels and the amounts of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion. (A) Comparison between diabetic patients with Gilbert syndrome, GS (+), and those without it, GS (-). Due to their skewed distribution, serum hs-CRP levels (ng/mL) and the amounts of urinary 8-OHdG excretion (urinary 8-OHdG to creatinine ratio, µg/gCr) were log10 transformed before all analyses. (B) Correlation between total bilirubin levels and serum hs-CRP levels. Spearman correlation analysis: r=-0.213, P<0.0001.

• 

  Fig. 2 The mechanism underlying increased oxidative stress in diabetic vascular tissues and possible antioxidant therapies targeting its mechanism for inhibiting diabetic vascular complications. ARB, angiotensin II receptor blocker; PKC, protein kinase C; ATII, angiotensin II; GLP-1, glucagon-like peptide-1.

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