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

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.

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

“…Activation of mitophagy blocked caspase-3 activation and attenuated reperfusion-mediated death in renal tubular epithelial cells. This finding is similar to that in previous reports demonstrating mitophagy is protective for the reperfused kidney [57, 58]. Therefore, this evidence firmly establishes the central role of mitochondria and the subsequent mitochondrial damage that amplifies the damage signal for the reperfused kidney.…”

Upregulation of miR-382 contributes to renal fibrosis secondary to aristolochic acid-induced kidney injury via PTEN signaling pathway

“…In addition, our study demonstrated that the loss of PTEN expression in renal fibrosis, which has since been substantiated by many recent studies 14,18,41,42 . Both in vivo and in vitro, phosphorylation of AKT on Ser473 was increased as along with AA-induced kidney injury, which was consistent with previous studies 43 . In addition, we found impaired AKT activation with difference between Ser473 and Thr308 AKT phosphorylation during AKI-CKD transition, which also contributed to myocardial infarct size in 5/6 nephrectomy rats 43 .…”

Triptolide Suppresses Glomerular Mesangial Cell Proliferation in Diabetic Nephropathy Is Associated with Inhibition of PDK1/Akt/mTOR Pathway

“…Moreover, PDK1 is also involved in many physiology and pathology changes, such as basilar artery smooth muscle cells proliferation 35 , autosomal dominant polycystic kidney disease 36 and insulin resistance 37 . In addition, the role PDK1 plays in chronic kidney disease is drawing more and more attention 38 . Although, there were few studies reported that PDK1 might regulate the apoptosis of podocytes in DN 24 , 25 .…”