Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase.
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.
Fujii
Masakazu
M
Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Inoguchi
Toyoshi
T
Sasaki
Shuji
S
Maeda
Yasutaka
Y
Zheng
Jing
J
Kobayashi
Kunihisa
K
Takayanagi
Ryoichi
R
D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001663:Bilirubin / Q000097:blood*; D001664:Biliverdine / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006933:Hyperbilirubinemia, Hereditary / Q000150:complications / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011911:Rats, Gunn; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000975:Antioxidants; D001786:Blood Glucose; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D013481:Superoxides; D000804:Angiotensin II; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C498911:Nox4 protein, rat; D005947:Glucose; D001664:Biliverdine; D001663:Bilirubin