SIRT1 alleviates insulin resistance and respiratory distress in late preterm rats by activating QKI5-mediated PPARγ/PI3K/AKT pathway.

Abstract

Neonatal respiratory distress syndrome (NRDS) is a common complication of gestational diabetes mellitus (GDM) and late preterm births. Research suggests that SIRT1 was involved in LPS-induced acute respiratory distress syndrome, but its mechanism remains to be further explored. Here, pregnant rats were intraperitoneally injected with 45 mg/Kg streptozotocin at day 0 of gestation to induce GDM and injected with LPS at day 17 of gestation to induce late preterm birth. Pioglitazone (a PPARγ agonist) was administered from day 17 to parturition in GDM group, and it was administered for 3 days before LPS injection in late preterm birth group. SRT1720 (a SIRT1 activator) was administered by oral gavage from day 0 to day 17 in both groups. Our data showed that activation of SIRT1 or PPARγ alleviated the abnormal blood glucose metabolism and lung tissue injury, downregulated expression of surfactant proteins (SP-B and SP-C), and decreased activation of the PI3K/AKT pathway induced by GDM and late preterm birth in neonatal rats. Moreover, an insulin resistance model was established by treating primary AT-II cells with insulin. Activation of SIRT1 reversed insulin-induced reduction in cell proliferation, glucose consumption, SP-B and SP-C expression, and the activity of the PI3K/AKT pathway and increase in cellular inflammation and apoptosis. Mechanistically, SIRT1 upregulated PPARγ expression via deacetylation of QKI5, an RNA binding protein that can stabilize its target mRNA molecules, and then activated the PI3K/AKT pathway. In conclusion, SIRT1 promotes the expression of PPARγ via upregulation of QKI5 and activates the PI3K/AKT pathway, thus mitigating NRDS caused by GDM and late preterm birth.