Increased urinary losses of carnitine and decreased intramitochondrial coenzyme A in gentamicin-induced acute renal failure in rats.
BACKGROUND
This study examined whether carnitine deficiency is a risk factor and should be viewed as a mechanism during the development of gentamicin (GM)-induced ARF as well as exploring if carnitine supplementation could offer protection against this toxicity.


METHODS
Adult male Wistar albino rats were assigned to one of six treatment groups: group 1 (control) rats were given daily intraperitoneal (I.P.) injections of normal saline for 8 consecutive days; groups 2, 3 and 4 rats were given GM (80 mg/kg/day, I.P.), l-carnitine (200 mg/kg/day, I.P.) and d-carnitine (250 mg/kg/day, I.P.), respectively, for 8 consecutive days. Rats of group 5 (GM plus d-carnitine) received a daily I.P. injection of d-carnitine (250 mg/kg/day) 1 h before GM (80 mg/kg/day) for 8 consecutive days. Rats of group 6 (GM plus l-carnitine) received a daily I.P. injection of l-carnitine (200 mg/kg/day) 1 h before GM (80 mg/kg/day) for 8 consecutive days.


RESULTS
GM significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion, intramitochondrial acetyl-CoA and total nitrate/nitrite (NOx) and thiobarbituric acid reactive substances (TBARS) in kidney tissues and significantly decreased total carnitine, intramitochondrial CoA-SH, ATP, ATP/ADP and reduced glutathione (GSH) in kidney tissues. In carnitine-depleted rats, GM caused a progressive increase in serum creatinine, BUN and urinary carnitine excretion and a progressive decrease in total carnitine, intamitochondrial CoA-SH and ATP. Interestingly, l-carnitine supplementation resulted in a complete reversal of the increase in serum creatinine, BUN, urinary carnitine excretion and the decrease in total carnitine, intramitochondrial CoA-SH and ATP, induced by GM, to the control values. Moreover, the histopathological examination of kidney tissues confirmed the biochemical data, where l-carnitine prevents and d-carnitine aggravates GM-induced ARF.


CONCLUSIONS
(i) GM-induced nephrotoxicity leads to increased urinary losses of carnitine; (ii) carnitine deficiency is a risk factor and should be viewed as a mechanism during the development of GM-induced ARF; and (iii) carnitine supplementation ameliorates the severity of GM-induced kidney dysfunction by increasing the intramitochondrial CoA-SH/acetyl-CoA ratio and ATP production.
Al-Shabanah
Othman A
OA
Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Kingdom of Saudi Arabia.
Aleisa
Abdulaziz M
AM
Al-Yahya
Abdulaziz A
AA
Al-Rejaie
Salim S
SS
Bakheet
Saleh A
SA
Fatani
Amal G
AG
Sayed-Ahmed
Mohamed M
MM
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001806:Blood Urea Nitrogen; D002331:Carnitine / Q000494:pharmacology / Q000652:urine*; D003065:Coenzyme A / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005839:Gentamicins / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D005839:Gentamicins; D000255:Adenosine Triphosphate; D003404:Creatinine; D002331:Carnitine; D003065:Coenzyme A