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

Masakazu Fujii, Toyoshi Inoguchi, Shuji Sasaki, Yasutaka Maeda, Jing Zheng, Kunihisa Kobayashi, Ryoichi Takayanagi

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

We recently found a markedly lower prevalence of vascular complications, including kidney disease, in diabetic patients with Gilbert syndrome, a congenital form of hyperbilirubinemia, suggesting a beneficial effect of bilirubin (BIL) on diabetic nephropathy. To directly examine this, we determined whether hereditary hyperbilirubinemic Gunn j/j rats and biliverdin (BVD)-treated diabetic db/db mice were resistant to the development of renal disease. Both rodent models had less albuminuria and complete protection against the progression of mesangial expansion accompanied by normalization of transforming growth factor-Β1 and fibronectin expression. Simultaneously, there was normalization of urinary and renal oxidative stress markers, and the expression of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits in the kidney. In cultured vascular endothelial and mesangial cells, BIL and BVD significantly inhibited NADPH-dependent superoxide production, and both high glucose-and angiotensin II-induced production of reactive oxygen species. Collectively, our findings suggest that BIL and BVD may protect against diabetic nephropathy and may lead to novel antioxidant therapies for diabetic nephropathy.

Original languageEnglish
Pages (from-to)905-919
Number of pages15
JournalKidney International
Volume78
Issue number9
DOIs
Publication statusPublished - Nov 2010

Fingerprint

Biliverdine
Diabetic Nephropathies
NADP
Bilirubin
Rodentia
Oxidoreductases
Down-Regulation
Kidney
Gilbert Disease
Albuminuria
Hyperbilirubinemia
Mesangial Cells
Transforming Growth Factors
Fibronectins
Superoxides
Angiotensin II
Blood Vessels
Reactive Oxygen Species
Oxidative Stress
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Fujii, M., Inoguchi, T., Sasaki, S., Maeda, Y., Zheng, J., Kobayashi, K., & Takayanagi, R. (2010). Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney International, 78(9), 905-919. https://doi.org/10.1038/ki.2010.265

Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. / Fujii, Masakazu; Inoguchi, Toyoshi; Sasaki, Shuji; Maeda, Yasutaka; Zheng, Jing; Kobayashi, Kunihisa; Takayanagi, Ryoichi.

In: Kidney International, Vol. 78, No. 9, 11.2010, p. 905-919.

Research output: Contribution to journalArticle

Fujii, M, Inoguchi, T, Sasaki, S, Maeda, Y, Zheng, J, Kobayashi, K & Takayanagi, R 2010, 'Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase', Kidney International, vol. 78, no. 9, pp. 905-919. https://doi.org/10.1038/ki.2010.265
Fujii, Masakazu ; Inoguchi, Toyoshi ; Sasaki, Shuji ; Maeda, Yasutaka ; Zheng, Jing ; Kobayashi, Kunihisa ; Takayanagi, Ryoichi. / Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. In: Kidney International. 2010 ; Vol. 78, No. 9. pp. 905-919.
@article{bc58958b8bce4f838e804811c16c524c,
title = "Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase",
abstract = "We recently found a markedly lower prevalence of vascular complications, including kidney disease, in diabetic patients with Gilbert syndrome, a congenital form of hyperbilirubinemia, suggesting a beneficial effect of bilirubin (BIL) on diabetic nephropathy. To directly examine this, we determined whether hereditary hyperbilirubinemic Gunn j/j rats and biliverdin (BVD)-treated diabetic db/db mice were resistant to the development of renal disease. Both rodent models had less albuminuria and complete protection against the progression of mesangial expansion accompanied by normalization of transforming growth factor-Β1 and fibronectin expression. Simultaneously, there was normalization of urinary and renal oxidative stress markers, and the expression of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits in the kidney. In cultured vascular endothelial and mesangial cells, BIL and BVD significantly inhibited NADPH-dependent superoxide production, and both high glucose-and angiotensin II-induced production of reactive oxygen species. Collectively, our findings suggest that BIL and BVD may protect against diabetic nephropathy and may lead to novel antioxidant therapies for diabetic nephropathy.",
author = "Masakazu Fujii and Toyoshi Inoguchi and Shuji Sasaki and Yasutaka Maeda and Jing Zheng and Kunihisa Kobayashi and Ryoichi Takayanagi",
year = "2010",
month = "11",
doi = "10.1038/ki.2010.265",
language = "English",
volume = "78",
pages = "905--919",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase

AU - Fujii, Masakazu

AU - Inoguchi, Toyoshi

AU - Sasaki, Shuji

AU - Maeda, Yasutaka

AU - Zheng, Jing

AU - Kobayashi, Kunihisa

AU - Takayanagi, Ryoichi

PY - 2010/11

Y1 - 2010/11

N2 - We recently found a markedly lower prevalence of vascular complications, including kidney disease, in diabetic patients with Gilbert syndrome, a congenital form of hyperbilirubinemia, suggesting a beneficial effect of bilirubin (BIL) on diabetic nephropathy. To directly examine this, we determined whether hereditary hyperbilirubinemic Gunn j/j rats and biliverdin (BVD)-treated diabetic db/db mice were resistant to the development of renal disease. Both rodent models had less albuminuria and complete protection against the progression of mesangial expansion accompanied by normalization of transforming growth factor-Β1 and fibronectin expression. Simultaneously, there was normalization of urinary and renal oxidative stress markers, and the expression of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits in the kidney. In cultured vascular endothelial and mesangial cells, BIL and BVD significantly inhibited NADPH-dependent superoxide production, and both high glucose-and angiotensin II-induced production of reactive oxygen species. Collectively, our findings suggest that BIL and BVD may protect against diabetic nephropathy and may lead to novel antioxidant therapies for diabetic nephropathy.

AB - We recently found a markedly lower prevalence of vascular complications, including kidney disease, in diabetic patients with Gilbert syndrome, a congenital form of hyperbilirubinemia, suggesting a beneficial effect of bilirubin (BIL) on diabetic nephropathy. To directly examine this, we determined whether hereditary hyperbilirubinemic Gunn j/j rats and biliverdin (BVD)-treated diabetic db/db mice were resistant to the development of renal disease. Both rodent models had less albuminuria and complete protection against the progression of mesangial expansion accompanied by normalization of transforming growth factor-Β1 and fibronectin expression. Simultaneously, there was normalization of urinary and renal oxidative stress markers, and the expression of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits in the kidney. In cultured vascular endothelial and mesangial cells, BIL and BVD significantly inhibited NADPH-dependent superoxide production, and both high glucose-and angiotensin II-induced production of reactive oxygen species. Collectively, our findings suggest that BIL and BVD may protect against diabetic nephropathy and may lead to novel antioxidant therapies for diabetic nephropathy.

UR - http://www.scopus.com/inward/record.url?scp=77958086954&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958086954&partnerID=8YFLogxK

U2 - 10.1038/ki.2010.265

DO - 10.1038/ki.2010.265

M3 - Article

C2 - 20686447

AN - SCOPUS:77958086954

VL - 78

SP - 905

EP - 919

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 9

ER -