Abstract
Fibrosis is a critical pathogenesis of organ dysfunction. Excessive production of reactive oxygen species (ROS) induces activation of undesirable cell signaling and oxidative injury resulting in onset and progression of fibrosis. Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) produces NADPH, an essential factor for the reduction of oxidized glutathione (GSSG), in the mitochondria of the cells. In this study we investigated a role for IDH2 in kidney fibrosis induced by unilateral ureteral obstruction (UUO) using IDH2-gene deleted mice (IDH2-/-) and wild-type mice (IDH2+/+). UUO induced fibrosis accompanied decrease in IDH2 in the kidney. UUO increased expression of α-smooth muscle actin and fibronectin, interstitium expansion, collagen deposition, and inflammatory cell accumulation. This fibrosis and related events in the IDH2-/- mice were significantly greater than those in the IDH2+/+ mice. UUO-induced oxidative stress was greater in the IDH2-/- mouse kidneys than that in the IDH2+/+ mouse kidneys. These results indicate that IDH2-gene deletion accelerates kidney fibrosis after UUO by increased oxidative stress, providing IDH2 as a therapeutic target for prevention and treatment of kidney fibrosis.
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