Department of Endocrinology, Zhongnan Hospital of Wuhan University, No.167 Donghu Road, Wuhan, 430071, Hubei, China.
Mol Biol Rep. 2024 Sep 21;51(1):1003. doi: 10.1007/s11033-024-09921-8.
Poricoic acid A (PAA), a major triterpenoid component of Poria cocos with anti-tumor, anti-fibrotic, anti-inflammatory, and immune-regulating activities, has been shown to induce podocyte autophagy in diabetic kidney disease (DKD) by downregulating FUN14 domain containing 1 (FUNDC1). This study aimed to identify the role of adenosine monophosphate-activated protein kinase alpha (AMPKα) in PAA-mediated phosphorylation of FUNDC1 in podocyte injury occurring in the pathogenesis of DKD.
A cellular model of renal podocyte injury was established by culturing MPC5 cells under high-glucose (HG) conditions. MPC5 cells were subjected to transfection with small interfering RNA (siRNA) targeting AMPKα or siRNA targeting FUNDC1, an AMPKα activator, or PAA. PAA treatment induced the phosphorylation of AMPKα in HG-cultured podocytes. AMPKα activation was implicated in the inhibitory effect of PAA on FUNDC phosphorylation in HG-cultured podocytes. Treatment targeting the AMPKα activator also significantly augmented proliferation, migration, mitochondrial membrane potential, and autophagy levels, while reducing apoptosis levels, inhibiting oxidative stress, and suppressing the release of proinflammatory factors in HG-cultured MPC5 cells. In contrast, insufficient expression of AMPKα reversed the effects of PAA on the proliferation, migration, and apoptosis of podocytes and further exacerbated the reduction of phosphorylated FUNDC1 expression in podocytes under HG conditions.
AMPKα is involved in the regulation of FUNDC1 phosphorylation by PAA in HG-induced podocyte injury. Furthermore, the AMPKα/FUNDC1 pathway plays a crucial regulatory role in HG-induced podocyte injury. These findings support AMPKα, FUNDC1, and the AMPKα/FUNDC1 pathway as targets for PAA intervention.
担子菌酸 A（PAA）是一种主要的担子菌三萜类成分，具有抗肿瘤、抗纤维化、抗炎和免疫调节作用，已被证明可通过下调 FUN14 结构域包含蛋白 1（FUNDC1）来诱导糖尿病肾病（DKD）中的足细胞自噬。本研究旨在确定腺苷单磷酸激活蛋白激酶α（AMPKα）在 PAA 介导的足细胞损伤发病机制中 FUNDC1 磷酸化中的作用。
通过在高糖（HG）条件下培养 MPC5 细胞建立肾足细胞损伤的细胞模型。用 AMPKα 的小干扰 RNA（siRNA）或 FUNDC1 的 siRNA、AMPKα 激活剂或 PAA 转染 MPC5 细胞。PAA 处理诱导 HG 培养的足细胞中 AMPKα 的磷酸化。AMPKα 激活参与 PAA 抑制 HG 培养的足细胞中 FUNDC 磷酸化的作用。针对 AMPKα 激活剂的治疗还显著增加了 HG 培养的 MPC5 细胞中的增殖、迁移、线粒体膜电位和自噬水平，同时降低了凋亡水平，抑制了氧化应激，并抑制了促炎因子的释放。相反，AMPKα 表达不足逆转了 PAA 对足细胞增殖、迁移和凋亡的影响，并进一步加剧了 HG 条件下足细胞中磷酸化 FUNDC1 表达的减少。
AMPKα 参与 PAA 在 HG 诱导的足细胞损伤中对 FUNDC1 磷酸化的调节。此外，AMPKα/FUNDC1 途径在 HG 诱导的足细胞损伤中发挥着关键的调节作用。这些发现支持 AMPKα、FUNDC1 和 AMPKα/FUNDC1 途径作为 PAA 干预的靶点。
