Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase

Fujii, Masakazu; Inoguchi, Toyoshi; Sasaki, Satoshi; Maeda, Yasutaka; Zheng, Jun; Kobayashi, Kazuo; Takayanagi, Ryoichi

doi:10.1038/ki.2010.265

Cited by 136 publications

(128 citation statements)

References 37 publications

(40 reference statements)

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“…In this context, we previously reported that biliverdin, a precursor of bilirubin, inhibited the development of renal abnormalities in db/db mouse, a rodent model of Type 2 diabetes, by inhibiting oxidative stress (6). Taken together, these findings indicate that increasing bilirubin levels may represent a novel therapeutic approach to prevent diabetic nephropathy.…”

mentioning

confidence: 84%

Phycocyanin and phycocyanobilin fromSpirulina platensisprotect against diabetic nephropathy by inhibiting oxidative stress

Zheng

Inoguchi

Sasaki

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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178

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We and other investigators have reported that bilirubin and its precursor biliverdin may have beneficial effects on diabetic vascular complications, including nephropathy, via its antioxidant effects. Here, we investigated whether phycocyanin derived from Spirulina platensis, a blue-green algae, and its chromophore phycocyanobilin, which has a chemical structure similar to that of biliverdin, protect against oxidative stress and renal dysfunction in db/db mice, a rodent model for Type 2 diabetes. Oral administration of phycocyanin (300 mg/kg) for 10 wk protected against albuminuria and renal mesangial expansion in db/db mice, and normalized tumor growth factor-β and fibronectin expression. Phycocyanin also normalized urinary and renal oxidative stress markers and the expression of NAD(P)H oxidase components. Similar antioxidant effects were observed following oral administration of phycocyanobilin (15 mg/kg) for 2 wk. Phycocyanobilin, bilirubin, and biliverdin also inhibited NADPH dependent superoxide production in cultured renal mesangial cells. In conclusion, oral administration of phycocyanin and phycocyanobilin may offer a novel and feasible therapeutic approach for preventing diabetic nephropathy.

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mentioning

confidence: 84%

Phycocyanin and phycocyanobilin fromSpirulina platensisprotect against diabetic nephropathy by inhibiting oxidative stress

Zheng

Inoguchi

Sasaki

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

178

132

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“…Bilirubin is known to be a potent endogenous antioxidant (2), and a recent study in rodents found a protective effect of bilirubin against DN through inhibition of oxidative stress by downregulation of renal NADPH oxidase (5).…”

Section: Discussionmentioning

confidence: 99%

Bilirubin and Progression of Nephropathy in Type 2 Diabetes: A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

et al. 2014

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Bilirubin, a potent endogenous antioxidant, was found to protect against the development of diabetic nephropathy (DN) in rodents. In humans, cross-sectional studies found an inverse relation between bilirubin and DN. We prospectively investigated whether bilirubin is associated with progression of DN toward end-stage renal disease (ESRD). To this end, we performed a post hoc analysis in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial with independent replication in the Irbesartan Diabetic Nephropathy Trial (IDNT). Subjects with type 2 diabetes and nephropathy with alanine aminotransferase, aspartate aminotransferase (AST), and bilirubin levels <1.5 times the upper limit of normal were included. The renal end point was defined as the composite of confirmed doubling of serum creatinine or ESRD. Bilirubin was inversely associated with the renal end point in RENAAL independent of age, sex, race, BMI, smoking, total cholesterol, diastolic blood pressure, HbA1c, treatment, estimated glomerular filtration rate, albumin-to-creatinine ratio, and AST. These results were confirmed in IDNT. This study indicates an independent inverse association of bilirubin with progression of nephropathy in RENAAL and IDNT. These data suggest a protective effect of bilirubin against progression of nephropathy in type 2 diabetes. The well-established role of bilirubin as an antioxidant is a potential explanation for the findings.

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“…It has been found that DNA oxidation and nitrosative stress with excessive production of nitric oxide and peroxynitrite were implicated in progression of chronic diabetic nephropathy [58]. It has been suggested that bilirubin and biliverdin can afford protection against diabetic nephropathy by blocking NADPH oxidase [59].…”

Section: Hyperglycemia As the Great Villain In Diabetes Mellitus: Indmentioning

confidence: 99%

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

Ferrari¹

2017

Integr Obesity Diabetes

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Oxidative and nitrosative stress reactions are implicated in cell and organ damage due to diabetes mellitus. In both type 1 and type 2 DM there is a massive oxidative and nitrosative stresses which have been associated with intensive changes on both antioxidant enzyme systems (SOD, CAT, GPx, GSH) and total antioxidant capacity (TAC) causing peroxidative damage to lipids, proteins, nucleic acids and carbohydrates which can be used as DM biomarkers. Molecular pathophysiology of diabetes mellitus envolves induction of the the NFkB and p38-MAPK cell signaling pathways by Rac, TNF-α, TLR4, decrease of antioxidant defenses, and direct mitochondrial damage. Knowledge of molecular pathways is essential for research of newer preventive and therapeutic approaches in diabetes mellitus complications (atherosclerosis, myocardial damage, endothelial dysfunction, and renal failure).urine, feces, tissue sample), vegetable or fruit extract or even foods or pharmaceuticals [14][15][16].This article review and update the clinical, cellular, and molecular knowledge of free radicals and antioxidant defenses in diabetes mellitus. Ethiopathogenesis of diabetes mellitus I and IIDiabetes mellitus has been conceptualized as a group of metabolic disorders characterized by hyperglicemia as a result of insulin secretion failure and/or lacking of insulin action on target cells. The chronic diabetic hyperglicemic state has been related to long-term organ damage especially to the heart, endothelium and blood vessels, nerves, kidney, and eyes [17][18][19].

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Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase

Cited by 136 publications

References 37 publications

Phycocyanin and phycocyanobilin fromSpirulina platensisprotect against diabetic nephropathy by inhibiting oxidative stress

Phycocyanin and phycocyanobilin fromSpirulina platensisprotect against diabetic nephropathy by inhibiting oxidative stress

Bilirubin and Progression of Nephropathy in Type 2 Diabetes: A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

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