Submitted on September 24, 2008
Revised on January 18, 2009
Accepted on February 8, 2009
Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats
Takanori Kumagai1, Masaomi Nangaku2, Ichiro Kojima, Ryoji Nagai3, Julie R. Ingelfinger4, Toshio Miyata5, Toshiro Fujita1, and Reiko Inagi1*
1 University of Tokyo School of Medicine
2 University of Tokyo
3 Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University,
4 Pediatric Nephrology Unit, MassGeneral Hospital for Children at Massachusetts General Hospital, and Harvard Medical School, Boston, MA
5 Tohoku University School of Medicine
* To whom correspondence should be addressed. E-mail: inagi-npr{at}umin.ac.jp.
Methylglyoxal (MG), a highly reactive carbonyl compound generated by carbohydrate oxidation and glycolysis, is the major precursor of protein glycation and induces cytotoxicity leading to apoptosis. Although recent studies have emphasized that MG accumulates in not only chronic oxidative stress-related diseases but also acute hypoxic conditions, the pathogenic contribution of MG in acute diseases is unclear. MG is efficiently metabolized by the glyoxalase system, namely glyoxalase I. We investigated the pathophysiological role of glyoxalase I as an MG detoxifier in rat renal ischemia-reperfusion (I/R) injury. I/R-induced tubulointerstitial injury was associated with a deterioration in renal glyoxalase I activity independent of its cofactor, GSH, as well as an increase in renal MG level. In in vitro studies, knockdown of glyoxalase I by siRNA transfection in rat tubular cells exacerbated cell death by hypoxia-reoxygenation compared to control cells. We also examined whether glyoxalase I overexpression prevented renal I/R damage in rats overexpressing human glyoxalase I with enzyme activity in the kidney 17-fold higher than in wild-type. The histological and functional manifestations of I/R in these rats were significantly ameliorated in association with a decrease in intracellular MG adduct accumulation, oxidative stress and tubular cell apoptosis. In conclusion, glyoxalase I exerts renoprotective effects in renal I/R injury via a reduction in MG accumulation in tubular cells.
