Superoxide dismutase-3 promotes full expression of the EPO response to hypoxia.
Extracellular superoxide dismutase (SOD3) is the primary extracellular enzymatic scavenger of superoxide ((.)O(2)(-)). SOD3's expression is highest in the kidney, but its distribution and biologic functions there are unknown. To investigate the function of renal SOD3, we colocalized it with erythropoietin (EPO) to proximal tubules using in situ hybridization and immunohistochemistry. We then exposed 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 hypoxia preceded at 2 hours by less accumulation of nuclear hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) protein. Meanwhile KO mice exposed to hypoxia showed increases in renal mRNA for superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) and early significant increases in glutathione disulfide (GSSG)/glutathione (GSH), a marker of oxidative stress, compared with Wt mice. Plasma nitrite/nitrate and renal 3-nitrotyrosine (3-NTyr), indicating 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 alpha and its target gene EPO in mouse kidney is regulated closely by the oxidant/antioxidant equilibrium involving SOD3, thus identifying renal SOD3 as a regulatory element in the body's innate adaptation to hypoxia.
Suliman
Hagir B
HB
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Ali
Mervat
M
Piantadosi
Claude A
CA
D000818:Animals; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006400:Hematocrit; D000860:Hypoxia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007668:Kidney / Q000201:enzymology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D014157:Transcription Factors; D004921:Erythropoietin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D005978:Glutathione; D019803:Glutathione Disulfide