Abstract
We determined whether endothelial nitric oxide synthase (eNOS) plays an important role in the renal protective effect of ischemic preconditioning (IP) against the ischemia/reperfusion-induced acute renal failure (ARF) by using eNOS-deficient (eNOS-/-) and wild-type (eNOS+/+) mice. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. IP, which consists of three cycles of 2-min ischemia followed by 5-min reperfusion, was performed prior to 45-min ischemia. In eNOS+/+ mice, IP treatment markedly attenuated the ischemia/reperfusion-induced renal dysfunction and significantly improved histological renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Constitutive nitric oxide synthase activity in the kidney without IP was markedly decreased 6 h after reperfusion, but this decreased response was not observed in eNOS+/+ mice with IP treatment. The improvement of renal dysfunction in eNOS+/+ mice with IP treatment was abolished by pretreatment with NG-nitro-l-arginine, a nonselective NOS inhibitor, whereas aminoguanidine, an inducible NOS inhibitor, had no effect. Finally, no protective effects of IP on ischemia/reperfusion-induced renal dysfunction and histological damage were observed in eNOS-/- mice. These findings strongly support the view that eNOS-mediated NO production plays a pivotal role in the protective effect of IP on ischemia/reperfusion-induced ARF.
Footnotes
-
This work was supported by a Grant-in-Aid for High Technology Research and a Grant-in-Aid for Scientific Research 14570092 (to Y.M.) from the Ministry of Education, Science, Sports, and Culture of Japan.
-
doi:10.1124/jpet.104.074427.
-
ABBREVIATIONS: I/R, ischemia/reperfusion; IP, ischemic preconditioning; PKC, protein kinase C; K+ATP channel, ATP-sensitive potassium channel; NO, nitric oxide; NOS, NO synthase; nNOS, neuronal NOS; eNOS, endothelial NOS; iNOS, inducible NOS; cNOS, constitutive NOS; ARF, acute renal failure; NO-ARG, NG-nitro-l-arginine; BUN, blood urea nitrogen; Pcr, plasma creatinine concentration; Uosm, urinary osmolality; UF, urine flow.
- Received July 16, 2004.
- Accepted August 12, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|