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 small interference RNA transfection in rat tubular cells exacerbated cell death by
hypoxia-reoxygenation compared with 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.