HEMATOPOIESIS Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia

(SOD3) is the primary extracellular enzy-matic scavenger of superoxide (O2). SOD3’s expression is highest in the kid-ney, but its distribution and biologic func-tions there are unknown. To investigate the function of renal SOD3, we colocal-ized it with erythropoietin (EPO) to proxi-mal tubules using in situ hybridization and immunohistochemistry. We then ex-posed wild-type (Wt) and SOD3 knock-out (KO) mice to hypoxia and found a late hematocrit response in the KO strain. EPO mRNA expression was attenuated in KO mice during the first 6 hours of hyp-oxia preceded at 2 hours by less accumu-lation of nuclear hypoxia-inducible tran-scription factor 1 (HIF-1) protein. Meanwhile KO mice exposed to hypoxia showed increases in renal mRNA for su-peroxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) and early significant increases in glutathione disulfide (GSSG)/glutathione (GSH), a marker of oxidative stress, com-pared with Wt mice. Plasma nitrite/nitrate and renal 3-nitrotyrosine (3-NTyr), indicat-ing peroxynitrite formation, increased later in hypoxia, and renal endothelial nitric oxide synthase protein induction was similar in both strains. These data show that hypoxic activation of HIF-1 and its target gene EPO in mouse kidney is regulated closely by the oxidant/antioxi-dant equilibrium involving SOD3, thus identifying renal SOD3 as a regulatory element in the body’s innate adaptation to hypoxia. (Blood. 2004;104:43-50) © 2004 by The American Society of Hematolog