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 journalArticlepeer-review

    127 Citations (Scopus)


    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
    Issue number9
    Publication statusPublished - Nov 2010

    All Science Journal Classification (ASJC) codes

    • Nephrology


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