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1 Animal Science, University of Manitoba, Winnipeg, Canada
2 Physiology, University of Manitoba, Winnipeg, Canada
3 Animal Science and Physiology, University of Manitoba, Winnipeg, Canada
* To whom correspondence should be addressed. E-mail: karmino{at}sbrc.ca.
Ischemia followed by reperfusion is a major cause for renal injury in both native kidney and renal allograft. 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 kidney. In this study, we investigated the role of Hcy in ischemia/reperfusion-induced renal injury. Left kidney of Sprague-Dawley rat was subjected to either 30-minute or 1 hour ischemia followed by 1-hour or 24-hour 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-fold 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-
-synthase (CBS), 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 hour of reperfusion. However, such a protective effect was not sustained after 24 hours 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.
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