Abstract
We examined the renoprotective effects of l-carnosine (β-alanyl-l-histidine) on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. In vehicle (0.9% saline)-treated rats, renal sympathetic nerve activity (RSNA) was significantly augmented during the renal ischemia, and renal function was markedly decreased at 24 h after reperfusion. Intracerebroventricular injection of l-carnosine (1.5 and 5 pmol/rat) to ischemic ARF rats dose-dependently suppressed the augmented RSNA during ischemia and the renal injury at 24 h after reperfusion. N-α-Acetyl-l-carnosine [N-acetyl-β-alanyl-l-histidine; 5 pmol/rat intracerebroventricular (i.c.v.)], which is resistant to enzymatic hydrolysis by carnosinase, did not affect the renal injury, and l-histidine (5 pmol/rat i.c.v.), a metabolite cleaved from l-carnosine by carnosinase, ameliorated the I/R-induced renal injury. Furthermore, a selective histamine H3 receptor antagonist, thioperamide (30 nmol/rat i.c.v.) eliminated the preventing effects by l-carnosine (15 nmol/rat intravenously) on ischemic ARF. In contrast, a selective H3 receptor agonist, R-α-methylhistamine (5 pmol/rat i.c.v.), prevented the I/R-induced renal injury as well as l-carnosine (5 pmol/rat) did. These results indicate that l-carnosine prevents the development of I/R-induced renal injury, and the effect is accompanied by suppressing the enhanced RSNA during ischemia. In addition, the present findings suggest that the renoprotective effect of l-carnosine on ischemic ARF is induced by its conversion to l-histidine and l-histamine and is mediated through the activation of histamine H3 receptors in the central nervous system.
Footnotes
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This study was supported in part by a “High-Tech Research Center” Project for Private Universities and a matching fund subsidy from the Ministry of Education, Culture, Sports, Science and Technology (2002–2006).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.110122.
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ABBREVIATIONS: I/R, ischemia/reperfusion; ARF, acute renal failure; RSNA, renal sympathetic nerve activity; NE, norepinephrine; BUN, blood urea nitrogen; Pcr, plasma creatinine concentration; Ccr, creatinine clearance; UF, urine flow; FENa, fractional excretion of sodium; Uosm, urinary osmolarity; R-HA, R-α-methylhistamine.
- Received June 28, 2006.
- Accepted August 15, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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