Title

Mechanisms of antioxidant and pro-oxidant effects of α-lipoic acid in the diabetic and nondiabetic kidney

Document Type

Journal Article

Publication Date

1-1-2005

Journal

Kidney International

Volume

67

Issue

4

DOI

10.1111/j.1523-1755.2005.00214.x

Keywords

Diabetes; Kidney; Oxidative stress; α-lipoic acid

Abstract

Background. α-Lipoic acid is a potent antioxidant that improves renal function in diabetes by lowering glycemia, however, the mechanisms by which α-lipoic acid exerts its antioxidant effects are not completely understood. Methods. Metabolic parameters, renal function, and morphology, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunit expression were analyzed in nondiabetic and streptozotocin-induced diabetic rats fed normal rat chow (control) with or without α-lipoic acid (30 mg/kg body weight) for 12 weeks. Results. Blood glucose was increased with diabetes (nondiabetic + control 89 ± 3 mg/dL and diabetic + control 336 ± 28 mg/dL) and was similar with α-lipoic acid treatment (diabetic + α-lipoic acid 351 ± 14 mg/dL). In contrast, α-lipoic acid attenuated albuminuria (nondiabetic + control 8.9 ± 1.3 mg/day; diabetic + control 28.1 ± 4.6 mg/day; and diabetic + α-lipoic acid 17.8 ± 1.2 mg/day) associated with diabetes. Similarly, α-lipoic acid attenuated glomerulosclerosis (nondiabetic + control 0.22 ± 0.01; diabetic + control 0.55 ± 0.04; diabetic + α-lipoic acid 0.36 ± 0.03), tubulointerstitial fibrosis (nondiabetic + control 0.42 ± 0.18; diabetic + control 1.52 ± 0.05; diabetic + α-lipoic acid 1.10 ± 0.05), superoxide anion (O2-) generation (nondiabetic + control 15.8 ± 1.7; diabetic + control 87.1 ± 3.5; diabetic + α-lipoic acid 25.5 ± 3.3 RLU/mg protein), and urine 8-isoprostane (8-iso) excretion (nondiabetic + control 7.4 ± 1.4; diabetic + control 26.0 ± 4.5; diabetic + α-lipoic acid 19.6 ± 5.6 ng/day) associated with diabetes. α-Lipoic acid also reduced kidney expression of NADPH oxidase subunits p22phox and p47phox. Surprisingly, α-lipoic acid appears to cause pro-oxidant effects in nondiabetic animals, resulting in increased albuminuria (nondiabetic + α-lipoic acid 14.2 ± 1.2 mg/day), increase in plasma creatinine levels (nondiabetic + control 59 ± 6; diabetic + control 68 ± 6; nondiabetic + α-lipoic acid 86 ± 9; diabetic + α-lipoic acid 69 ± 7 μmol/L), exacerbated glomerulosclerosis and tubulointerstitial fibrosis, increased O2- generation, up-regulated p22phox and p47phox expression and increased 8-iso excretion. Conclusion. We conclude that α-lipoic acid improves albuminuria and pathology in diabetes by reducing oxidative stress, while in healthy animals, α-lipoic acid may act as a pro-oxidant, contributing to renal dysfunction. © 2005 by the International Society of Nephrology.

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