alpha-Lipoic acid prevents cisplatin-induced acute kidney injury in rats.
BACKGROUND
Cisplatin-induced nephropathy has been related to increased lipid peroxide formation and decreased activity of antioxidant enzymes in the kidney. The present study aimed to examine whether treatment with alpha-lipoic acid (alpha-LA) prevents the cisplatin-induced nephrotoxicity.


METHODS
Two groups of rats were treated with cisplatin, one of which being cotreated with alpha-LA. The control group was treated with vehicle only. Four days later, the expression of aquaporins and sodium transporters was determined in the kidney by immunoblotting and immunohistochemistry. The arginine vasopressin-stimulated generation of cAMP was measured by radioimmunoassay. The expression of nitric oxide synthases (NOS) was determined by immunoblotting. The mRNA expression of endothelin-1 (ET-1) and tumour necrosis factor (TNF)-alpha was measured by real-time PCR. Apoptosis was examined by TUNEL staining.


RESULTS
Following the treatment with cisplatin, urinary volume and fractional excretion of sodium increased. Accordingly, the expression of aquaporins 1-3, Na,K-ATPase, NHE3 and NKCC2 was decreased. The expression of adenylyl cyclase VI and vasopressin-stimulated cAMP generation was decreased. The expression of inducible NOS was increased, while that of endothelial NOS decreased. The ET-1 expression was increased. TUNEL-positive cells were increased, in association with an increased expression of TNF-alpha. alpha-LA treatment prevented dysregulation of these parameters and resumed the renal function.


CONCLUSIONS
alpha-LA may prevent the cisplatin-induced nephrotoxicity, possibly through preserving the activities of NO and ET systems and inhibiting the development of apoptosis.
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Eun Hui
EH
Bae
JongUn
J
Lee
Seong Kwon
SK
Ma
In Jin
IJ
Kim
Jørgen
J
Frøkiaer
Søren
S
Nielsen
Sun Young
SY
Kim
Soo Wan
SW
Kim
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020346:Aquaporins / Q000378:metabolism; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016232:Endothelins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000975:Antioxidants; D020346:Aquaporins; D016232:Endothelins; D012333:RNA, Messenger; D008063:Thioctic Acid; D019001:Nitric Oxide Synthase; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D000254:Sodium-Potassium-Exchanging ATPase; D002945:Cisplatin