TY - JOUR
T1 - Reduced expression of lipoic acid synthase accelerates diabetic nephropathy
AU - Yi, Xianwen
AU - Xu, Longquan
AU - Hiller, Sylvia
AU - Kim, Hyung Suk
AU - Nickeleit, Volker
AU - James, Leighton R.
AU - Maeda, Nobuyo
PY - 2012/1
Y1 - 2012/1
N2 - Oxidative stress contributes to the pathogenesis of diabetic nephropathy. In mitochondria, lipoic acid synthase produces a-lipoic acid, an antioxidant and an essential cofactor in a-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 hadmore overt diabetic nephropathy, includingmicroalbuminuria, 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 diabeticmice with reduced lipoic acid production. These results suggest that lipoic acid synthase deficiency increases oxidative stress and accelerates the development of diabetic nephropathy.
AB - Oxidative stress contributes to the pathogenesis of diabetic nephropathy. In mitochondria, lipoic acid synthase produces a-lipoic acid, an antioxidant and an essential cofactor in a-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 hadmore overt diabetic nephropathy, includingmicroalbuminuria, 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 diabeticmice with reduced lipoic acid production. These results suggest that lipoic acid synthase deficiency increases oxidative stress and accelerates the development of diabetic nephropathy.
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U2 - 10.1681/ASN.2011010003
DO - 10.1681/ASN.2011010003
M3 - Article
C2 - 22021711
AN - SCOPUS:84862937339
SN - 1046-6673
VL - 23
SP - 103
EP - 111
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 1
ER -