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Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease

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Abstract

Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56.3 ± 4.6 vs. 41.4 ± 2.0%). In SNx group, myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3β was significantly suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by Ku-0063794 significantly increased infarct size in the Sham group but not in the SNx group. There was no difference between the two groups in activities of mTORC2 and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit B55α, which specifically targets Akt-Thr308, was reduced by 24% in the SNx group. Knockdown of B55α by siRNA increased baseline p-Akt-Thr308 and blunted Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293 cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55α inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired Akt activation by insufficient Ser473 phosphorylation upon reperfusion contributes to infarct size enlargement by CKD.

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Author notes

  1. Toshiyuki Tobisawa and Toshiyuki Yano contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan

    Toshiyuki Tobisawa, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Yukishige Kimura, Satoko Ishikawa, Hidemichi Kouzu, Keitaro Nishizawa, Hideaki Yoshida & Tetsuji Miura

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  1. Toshiyuki Tobisawa
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  11. Tetsuji Miura
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Correspondence to Tetsuji Miura.

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The present study was supported by Grant-in-aid for Scientific Research (#2646113 and #16K09505) from the Japan Society for the Promotion of Science, Tokyo, Japan and by Grant for Research and Education 2015 from Sapporo Medical University, Sapporo, Japan.

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Tobisawa, T., Yano, T., Tanno, M. et al. Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease. Basic Res Cardiol 112, 31 (2017). https://doi.org/10.1007/s00395-017-0621-6

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