Detrimental role of homocysteine in renal ischemia-reperfusion injury.
Ischemia followed by reperfusion is a major cause for renal injury in both native kidney and renal allografts. Hyperhomocysteinemia, a condition of elevated plasma homocysteine (Hcy) level, is associated with cardiovascular diseases. Recent evidence suggests that Hcy, at higher levels, may be harmful to other organs such as the kidney. In this study, we investigated the role of Hcy in ischemia-reperfusion-induced renal injury. The left kidney of a Sprague-Dawley rat was subjected to either 30-min or 1-h ischemia followed by 1- or 24-h reperfusion. Ischemia-reperfusion caused a significant increase in peroxynitrite formation and lipid peroxidation in kidneys, which reflected oxidative stress. The number of apoptotic cells in those kidneys was also markedly increased. Hcy levels were elevated 2.9- and 1.5-fold in kidneys subjected to ischemia alone or ischemia-reperfusion, respectively. Further investigation revealed that elevation of Hcy level in the kidney upon ischemia-reperfusion was due to reduced activity of cystathionine-beta-synthase, a key enzyme in Hcy metabolism. Administration of anti-Hcy antibodies into the kidney not only abolished ischemia-reperfusion-induced oxidative stress and cell death in the kidneys but also restored renal function after 1 h of reperfusion. However, such a protective effect was not sustained after 24 h of reperfusion. In conclusion, ischemia-reperfusion impairs Hcy metabolism in the kidney. Hcy, at elevated levels, is capable of inducing oxidative stress and renal injury. Neutralization of Hcy with antibodies offers transient functional benefit against ischemia-reperfusion-induced oxidative stress and renal injury. These results suggest that Hcy may play a detrimental role in the kidney during ischemia-reperfusion.
Prathapasinghe
Gamika A
GA
Departments of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada.
Siow
Yaw L
YL
O
Karmin
K
D000818:Animals; D017209:Apoptosis; D003404:Creatinine / Q000097:blood; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D009392:Nephrectomy; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D006710:Homocysteine; D013481:Superoxides; D009569:Nitric Oxide; D003404:Creatinine