The role of the polyol pathway in acute kidney injury caused by hindlimb ischaemia in mice.
The polyol pathway, a collateral glycolytic process, previously considered to be active in high glucose milieu, has recently been proposed to play a crucial role in ischaemia/reperfusion tissue injury. In this study, we explored the role of the polyol pathway in acute kidney injury (AKI), a life-threatening condition, caused by hindlimb ischaemia, and determined if inhibition of the polyol pathway by aldose reductase (AR) inhibitor is beneficial for this serious disorder. Mice 8 weeks of age rendered hindlimb ischaemic for 3 h by the clipping of major supporting arteries revealed marked muscle necrosis with accumulation of sorbitol and fructose in ischaemic muscles. Serum concentrations of blood urea nitrogen (BUN), creatinine phosphokinase (CPK), creatinine, tumour necrosis factor (TNF)-alpha as well as interleukin (IL)-6 were all elevated in these mice. Treatment with AR inhibitor (ARI) effectively suppressed muscle necrosis and accompanying inflammatory reactions and prevented renal failure. Similar to ARI-treated mice, AR-deficient mice were protected from severe ischaemic limb injury and renal failure, showing only modest muscle necrosis and significant suppression of serum markers of renal failure and inflammation. Thus, these findings suggest that the polyol pathway is implicated in AKI caused by ischaemic limb injury and that AR may be a potential therapeutic target for this condition.
Yagihashi
Soroku
S
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. yagihasi@cc.hirosaki-u.ac.jp
Mizukami
Hiroki
H
Ogasawara
Saori
S
Yamagishi
Shin-Ichiro
S
Nukada
Hitoshi
H
Kato
Noriaki
N
Hibi
Chihiro
C
Chung
Sookja
S
Chung
Stephen
S
D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006614:Hindlimb / Q000098:blood supply*; D048289:Imidazolidines / Q000627:therapeutic use; D007511:Ischemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000209:etiology / Q000517:prevention & control; D011108:Polymers / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D004791:Enzyme Inhibitors; D048289:Imidazolidines; D011108:Polymers; C024617:polyol; C077139:fidarestat; D000449:Aldehyde Reductase