Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats.
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.
Kumagai
Takanori
T
Div. of Nephrology and Endocrinology, Univ. of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Nangaku
Masaomi
M
Kojima
Ichiro
I
Nagai
Ryoji
R
Ingelfinger
Julie R
JR
Miyata
Toshio
T
Fujita
Toshiro
T
Inagi
Reiko
R
D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002460:Cell Line; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress; D011765:Pyruvaldehyde / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D014162:Transfection; D015854:Up-Regulation
D034741:RNA, Small Interfering; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase; D005978:Glutathione