α-Lipoic acid protects diabetic apolipoprotein E-deficient mice from nephropathy.
OBJECTIVE
Both hyperglycemia and hyperlipidemia increase oxidative stress and contribute to the development of diabetic nephropathy (DN). We investigated the effects of α-lipoic acid, a natural antioxidant and a cofactor in the multienzyme complexes, on the development of DN in diabetic apolipoprotein E-deficient mice.


METHODS
Twelve-week-old male apoE-/- mice on C57BL/6J genetic background were made diabetic with injections of streptozotocin (STZ). STZ-treated diabetic apoE-/- mice and non-diabetic control were fed with a synthetic high-fat (HF) diet with or without lipoic acid (LA) supplementation. Multiple parameters including plasma glucose, cholesterol, oxidative stress markers, cytokines, and kidney cortex gene expression, and glomerular morphology were evaluated.


RESULTS
LA supplementation markedly protected the β cells, reduced cholesterol levels, and attenuated albuminuria and glomerular mesangial expansion in the diabetic mice. Renoprotection by LA was equally effective regardless of whether the dietary supplementation was started 4 weeks before, simultaneously with, or 4 weeks after the induction of diabetes by STZ. LA supplementation significantly improved DN and oxidative stress in the diabetic mice. Severity of albuminuria was positively correlated with level of thiobarbituric acid reactive substances (TBARs) in the kidney (r(2)=0.62, P<.05). Diabetes significantly changed the kidney expression of Rage, Sod2, Tgfb1 and Ctgf, Pdp2, nephrin, and Lias. LA supplementation corrected these changes except that it further suppressed the expression of the Lias gene coding for lipoic acid synthase.


CONCLUSIONS
Our data indicate that LA supplementation effectively attenuates the development and progression of DN through its antioxidant effect as well as enhances glucose oxidation.
Yi
Xianwen
X
Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, USA. xyi2000@med.unc.edu
Nickeleit
Volker
V
James
Leighton R
LR
Maeda
Nobuyo
N
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics*; D001794:Blood Pressure; D016207:Cytokines / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D050171:Dyslipidemias / Q000150:complications / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy; D004204:Joint Dislocations; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000187:drug effects; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D001057:Apolipoproteins E; D016207:Cytokines; D008063:Thioctic Acid
Cell Immunol. 2009;260(1):44-50
19766202
Curr Diab Rep. 2006 Dec;6(6):455-62
17118229
Prog Lipid Res. 1997 Mar;36(1):1-21
9373618
Diabetologia. 1998 Jul;41(7):784-90
9686919
J Nutr. 2009 Nov;139(11):2072-8
19759248
Treat Endocrinol. 2004;3(3):173-89
16026113
Hypertension. 1990 May;15(5):443-50
2185148
Biofactors. 1999;10(2-3):169-74
10609878
Food Chem Toxicol. 2009 Aug;47(8):2124-8
19500641
Am J Clin Nutr. 1998 Jan;67(1):50-7
9440375
Diabetes. 2006 Aug;55(8):2238-44
16873686
J Sci Food Agric. 2010 Jan 30;90(2):349-56
20355053
J Cell Physiol. 2010 Mar;222(3):669-75
19950211
Atherosclerosis. 2010 Aug;211(2):424-30
20347443
Lab Invest. 2002 Aug;82(8):999-1006
12177238
Biochimie. 2008 Mar;90(3):450-9
18157951
J Am Soc Nephrol. 2002 Jan;13(1):108-116
11752027
Diabetologia. 1982 Mar;22(3):194-8
6210590
Metabolism. 1997 Jul;46(7):763-8
9225829
Nephrol Dial Transplant. 2002 Dec;17(12):2099-107
12454219
Free Radic Biol Med. 1995 Aug;19(2):227-50
7649494
J Clin Invest. 2000 Feb;105(4):451-8
10683374
Diabetes Res Clin Pract. 2008 Nov 13;82 Suppl 1:S67-9
18926584
Free Radic Biol Med. 2001 Aug 1;31(3):331-5
11461770
Diabetes. 1999 Jan;48(1):1-9
9892215
Am J Physiol Renal Physiol. 2006 Jan;290(1):F214-22
16118394
J Clin Invest. 1998 Mar 1;101(5):1142-7
9486985
Biochemistry. 2007 Feb 27;46(8):2146-55
17274632
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10771-8
7971961
Nature. 1981 Nov 12;294(5837):158-60
7300898
J Clin Invest. 2002 May;109(9):1153-63
11994404
Diabetes. 2005 Jun;54(6):1615-25
15919781
Protein Sci. 1998 Jan;7(1):220-4
9514279