Department of Pharmacology, Chongqing Medical University, the Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
Department of Pharmacology, Chongqing Health Center for Women and Children Chongqing 400016, China.
Int J Biol Sci. 2021 Sep 21;17(14):3993-4004. doi: 10.7150/ijbs.60149. eCollection 2021.
Prostaglandin D2 (PGD2) is the most abundant prostaglandin in the brain, but its involvement in brain damage caused by type 2 diabetes (T2D) has not been reported. In the present study, we found that increased PGD2 content is related to the inhibition of autophagy, which aggravates brain damage in T2D, and may be involved in the imbalanced expression of the corresponding PGD2 receptors DP1 and DP2. We demonstrated that DP2 inhibited autophagy and promotedT2D-induced brain damage by activating the PI3K/AKT/mTOR pathway, whereas DP1enhanced autophagy and amelioratedT2D brain damage by activating the cAMP/PKA pathway. In a T2D rat model, DP1 expression was decreased, and DP2 expression was increased; therefore, the imbalance in PGD2-DPs may be involved in T2D brain damage through the regulation of autophagy. However, there have been no reports on whether PKA can directly inhibit mTOR. The PKA catalytic subunit (PKA-C) has three subtypes (α, β and γ), and γ is not expressed in the brain. Subsequently, we suggested that PKA could directly interact with mTOR through PKA-C(α) and PKA-C(β). Our results suggest that the imbalance in PGD2-DPs is related to changes in autophagy levels in T2D brain damage, and PGD2 is involved in T2D brain damage by promoting autophagy via DP1-PKA/mTOR and inhibiting autophagy via DP2-PI3K/AKT/mTOR.
前列腺素 D2（PGD2）是大脑中含量最丰富的前列腺素，但它在 2 型糖尿病（T2D）引起的脑损伤中的作用尚未报道。在本研究中，我们发现 PGD2 含量的增加与自噬的抑制有关，这加剧了 T2D 中的脑损伤，并且可能与相应的 PGD2 受体 DP1 和 DP2 的失衡表达有关。我们证明 DP2 通过激活 PI3K/AKT/mTOR 通路抑制自噬并促进 T2D 引起的脑损伤，而 DP1 通过激活 cAMP/PKA 通路增强自噬并改善 T2D 脑损伤。在 T2D 大鼠模型中，DP1 的表达减少，DP2 的表达增加；因此，PGD2-DPs 的失衡可能通过调节自噬参与 T2D 脑损伤。然而，目前还没有关于 PKA 是否可以直接抑制 mTOR 的报道。PKA 催化亚基（PKA-C）有三种亚型（α、β 和 γ），而 γ 在脑中不表达。随后，我们提出 PKA 可以通过 PKA-C（α）和 PKA-C（β）与 mTOR 直接相互作用。我们的结果表明，PGD2-DPs 的失衡与 T2D 脑损伤中自噬水平的变化有关，PGD2 通过 DP1-PKA/mTOR 促进自噬，通过 DP2-PI3K/AKT/mTOR 抑制自噬，从而参与 T2D 脑损伤。
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