Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes

Yoshihito Iuchi, Futoshi Okada, Rina Takamiya, Noriko Kibe, Satoshi Tsunoda, Osamu Nakajima, Kazuyo Toyoda, Ritsuko Nagae, Makoto Suematsu, Tomoyoshi Soga, Koji Uchida, Junichi Fujii

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Oxidative stress has been implicated as a cause of various diseases such as anaemia. We found that the SOD1 [Cu,Zn-SOD (superoxide dismutase)] gene deficiency causes anaemia, the production of autoantibodies against RBCs (red blood cells) and renal damage. In the present study, to further understand the role of oxidative stress in the autoimmune response triggered by SOD1 deficiency, we generated mice that had the hSOD1 (human SOD1) transgene under regulation of the GATA-1 promoter, and bred the transgene onto the SOD1-/-background (SOD1-/ -;hSOD1tg/+). The lifespan of RBCs, levels of intracellular reactive oxygen species, and RBC content in SOD1-/-;hSOD1tg/+ mice, were approximately equivalent to those of SOD1+/+ mice. The production of antibodies against lipid peroxidation products, 4-hydroxy-2-nonenal and acrolein, as well as autoantibodies against RBCs and carbonic anhydrase II were elevated in the SOD1-/-mice, but were suppressed in the SOD1-/-;hSOD1tg/+ mice. Renal function, as judged by blood urea nitrogen, was improved in the transgenic mice. These results rule out the involvement of a defective immune system in the autoimmune response of SOD1-deficient mice, because SOD1-/ -;hSOD1tg/+ mice carry the hSOD1 protein only in RBCs. Metabolomic analysis indicated a shift in glucose metabolism to the pentose phosphate pathway and a decrease in the energy charge potential of RBCs in SOD1-deficient mice. We conclude that the increase in reactive oxygen species due to SOD1 deficiency accelerates RBC destruction by affecting carbon metabolism and increasing oxidative modification of lipids and proteins. The resulting oxidation products are antigenic and, consequently, trigger autoantibody production, leading to autoimmune responses.

Original languageEnglish
Pages (from-to)313-320
Number of pages8
JournalBiochemical Journal
Volume422
Issue number2
DOIs
Publication statusPublished - 2009 Sep 1

Fingerprint

Autoimmunity
Transgenic Mice
Anemia
Blood
Erythrocytes
Autoantibodies
Oxidative stress
Transgenes
Metabolism
Reactive Oxygen Species
Oxidative Stress
Carbonic Anhydrase II
Acrolein
Pentoses
Kidney
Lipids
Pentose Phosphate Pathway
Metabolomics
Immune system
Blood Urea Nitrogen

Keywords

  • Autoantibody
  • Oxidative stress
  • Superoxide dismutase
  • Transgenic rescue

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Iuchi, Y., Okada, F., Takamiya, R., Kibe, N., Tsunoda, S., Nakajima, O., ... Fujii, J. (2009). Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes. Biochemical Journal, 422(2), 313-320. https://doi.org/10.1042/BJ20090176

Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes. / Iuchi, Yoshihito; Okada, Futoshi; Takamiya, Rina; Kibe, Noriko; Tsunoda, Satoshi; Nakajima, Osamu; Toyoda, Kazuyo; Nagae, Ritsuko; Suematsu, Makoto; Soga, Tomoyoshi; Uchida, Koji; Fujii, Junichi.

In: Biochemical Journal, Vol. 422, No. 2, 01.09.2009, p. 313-320.

Research output: Contribution to journalArticle

Iuchi, Y, Okada, F, Takamiya, R, Kibe, N, Tsunoda, S, Nakajima, O, Toyoda, K, Nagae, R, Suematsu, M, Soga, T, Uchida, K & Fujii, J 2009, 'Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes', Biochemical Journal, vol. 422, no. 2, pp. 313-320. https://doi.org/10.1042/BJ20090176
Iuchi, Yoshihito ; Okada, Futoshi ; Takamiya, Rina ; Kibe, Noriko ; Tsunoda, Satoshi ; Nakajima, Osamu ; Toyoda, Kazuyo ; Nagae, Ritsuko ; Suematsu, Makoto ; Soga, Tomoyoshi ; Uchida, Koji ; Fujii, Junichi. / Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes. In: Biochemical Journal. 2009 ; Vol. 422, No. 2. pp. 313-320.
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