Mechanisms of antioxidant and pro-oxidant effects of alpha-lipoic acid in the diabetic and nondiabetic kidney.
BACKGROUND
alpha-Lipoic acid is a potent antioxidant that improves renal function in diabetes by lowering glycemia, however, the mechanisms by which alpha-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 alpha-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 alpha-lipoic acid treatment (diabetic +alpha-lipoic acid 351 +/- 14 mg/dL). In contrast, alpha-lipoic acid attenuated albuminuria (nondiabetic + control 8.9 +/- 1.3 mg/day; diabetic + control 28.1 +/- 4.6 mg/day; and diabetic +alpha-lipoic acid 17.8 +/- 1.2 mg/day) associated with diabetes. Similarly, alpha-lipoic acid attenuated glomerulosclerosis (nondiabetic + control 0.22 +/- 0.01; diabetic + control 0.55 +/- 0.04; diabetic +alpha-lipoic acid 0.36 +/- 0.03), tubulointerstitial fibrosis (nondiabetic + control 0.42 +/- 0.18; diabetic + control 1.52 +/- 0.05; diabetic +alpha-lipoic acid 1.10 +/- 0.05), superoxide anion (O(.-) (2)) generation (nondiabetic +control 15.8 +/- 1.7; diabetic +control 87.1 +/- 3.5; diabetic +alpha-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 +alpha-lipoic acid 19.6 +/- 5.6 ng/day) associated with diabetes. alpha-Lipoic acid also reduced kidney expression of NADPH oxidase subunits p22phox and p47phox. Surprisingly, alpha-lipoic acid appears to cause pro-oxidant effects in nondiabetic animals, resulting in increased albuminuria (nondiabetic +alpha-lipoic acid 14.2 +/- 1.2 mg/day), increase in plasma creatinine levels (nondiabetic + control 59 +/- 6; diabetic + control 68 +/- 6; nondiabetic +alpha-lipoic acid 86 +/- 9; diabetic +alpha-lipoic acid 69 +/- 7 mumol/L), exacerbated glomerulosclerosis and tubulointerstitial fibrosis, increased O(.-) (2) generation, up-regulated p22phox and p47phox expression and increased 8-iso excretion.


CONCLUSIONS
We conclude that alpha-lipoic acid improves albuminuria and pathology in diabetes by reducing oxidative stress, while in healthy animals, alpha-lipoic acid may act as a pro-oxidant, contributing to renal dysfunction.
Bhatti
Faizah
F
Department of Medicine, Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC 20057, USA.
Mankhey
Richard W
RW
Asico
Laureano
L
Quinn
Mark T
MT
Welch
William J
WJ
Maric
Christine
C
D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004195:Disease Models, Animal; D007668:Kidney / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology*; D051381:Rats; D012016:Reference Values; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D001786:Blood Glucose; D016877:Oxidants; D008063:Thioctic Acid