Reduced Expression of Lipoic Acid Synthase Accelerates Diabetic Nephropathy

Oxidative stress contributes to the pathogenesis of diabetic nephropathy. In mitochondria, lipoic acid synthase produces α-lipoic acid, an antioxidant and an essential cofactor in α-ketoacid dehydrogenase complexes, which participate in glucose oxidation and ATP generation. Administration of lipoic...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2012-01, Vol.23 (1), p.103-111
Main Authors: XIANWEN YI, LONGQUAN XU, HILLER, Sylvia, KIM, Hyung-Suk, NICKELEIT, Volker, JAMES, Leighton R, MAEDA, Nobuyo
Format: Article
Language:English
Subjects:
Animals
Associated diseases and complications
Basic Research
Biological and medical sciences
Blood Glucose - metabolism
Citrate (si)-Synthase - metabolism
Diabetes. Impaired glucose tolerance
Diabetic Nephropathies - blood
Diabetic Nephropathies - complications
Diabetic Nephropathies - enzymology
Diabetic Nephropathies - pathology
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Gene Expression
Hypertension - etiology
Kidney Tubules, Proximal - pathology
Kidneys
Male
Medical sciences
Mice
Mice, Inbred C57BL
Nephrology. Urinary tract diseases
Oxidative Stress
Phenotype
Sulfurtransferases - metabolism
Superoxides - metabolism
Urinary system involvement in other diseases. Miscellaneous
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Summary:Oxidative stress contributes to the pathogenesis of diabetic nephropathy. In mitochondria, lipoic acid synthase produces α-lipoic acid, an antioxidant and an essential cofactor in α-ketoacid dehydrogenase complexes, which participate in glucose oxidation and ATP generation. Administration of lipoic acid abrogates diabetic nephropathy in animal models, but whether lower production of endogenous lipoic acid promotes diabetic nephropathy is unknown. Here, we crossed mice heterozygous for lipoic acid synthase deficiency (Lias(+/-)) with Ins2(Akita/+) mice, a well characterized model of type 1 diabetes. Double mutant mice had more overt diabetic nephropathy, including microalbuminuria, glomerular basement thickening, mesangial matrix expansion, and hypertension, compared with Lias(+/+)Ins2(Akita/+) controls. We also identified proximal tubules as a major site for generation of superoxide anions during diabetic nephropathy. Mitochondria in proximal tubular cells were particularly sensitive to damage in diabetic mice with reduced lipoic acid production. These results suggest that lipoic acid synthase deficiency increases oxidative stress and accelerates the development of diabetic nephropathy.
ISSN:1046-6673
1533-3450
DOI:10.1681/ASN.2011010003