Cell Biology – Immunology – Pathology
Kidney International (2005) 67, 1371–1380; doi:10.1111/j.1523-1755.2005.00214.x
Mechanisms of antioxidant and pro-oxidant effects of 
-lipoic acid in the diabetic and nondiabetic kidney
FAIZAH BHATTI, RICHARD W MANKHEY, LAUREANO ASICO, MARK T QUINN, WILLIAM J WELCH and CHRISTINE MARIC
Department of Medicine, Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC; Department of Pediatrics, Georgetown University Medical Center, Washington, DC; and Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana
Correspondence: Christine Maric Ph.D., Department of Medicine, Division of Nephrology and Hypertension, Georgetown University Medical Center, 394 Bldg. D, 4000 Reservoir Rd. NW, Washington, DC 20057. E-mail:cm255@georgetown.edu
Received 29 July 2004; Revised 14 September 2004; Re-revised 5 October 2004; Accepted 25 October 2004.
Abstract
Mechanisms of antioxidant and pro-oxidant effects of 
-lipoic acid in the diabetic and nondiabetic kidney.
Background
-Lipoic acid is a potent antioxidant that improves renal function in diabetes by lowering glycemia, however, the mechanisms by which -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 -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 -lipoic acid treatment (diabetic +-lipoic acid 351 14 mg/dL). In contrast, -lipoic acid attenuated albuminuria (nondiabetic + control 8.9 1.3 mg/day; diabetic + control 28.1 4.6 mg/day; and diabetic +-lipoic acid 17.8 1.2 mg/day) associated with diabetes. Similarly, -lipoic acid attenuated glomerulosclerosis (nondiabetic + control 0.22 0.01; diabetic + control 0.55 0.04; diabetic +-lipoic acid 0.36 0.03), tubulointerstitial fibrosis (nondiabetic + control 0.42 0.18; diabetic + control 1.52 0.05; diabetic +-lipoic acid 1.10 0.05), superoxide anion (O
-2) generation (nondiabetic +control 15.8 1.7; diabetic +control 87.1 3.5; diabetic +-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 +-lipoic acid 19.6 5.6 ng/day) associated with diabetes. -Lipoic acid also reduced kidney expression of NADPH oxidase subunits p22phox and p47phox. Surprisingly, -lipoic acid appears to cause pro-oxidant effects in nondiabetic animals, resulting in increased albuminuria (nondiabetic +-lipoic acid 14.2 1.2 mg/day), increase in plasma creatinine levels (nondiabetic + control 59 6; diabetic + control 68 6; nondiabetic +-lipoic acid 86 9; diabetic +-lipoic acid 69 7 
mol/L), exacerbated glomerulosclerosis and tubulointerstitial fibrosis, increased O-2 generation, up-regulated p22phox and p47phox expression and increased 8-iso excretion.
Conclusion
We conclude that -lipoic acid improves albuminuria and pathology in diabetes by reducing oxidative stress, while in healthy animals, -lipoic acid may act as a pro-oxidant, contributing to renal dysfunction.
Keywords:
-lipoic acid, diabetes, kidney, oxidative stress
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