Increased thromboxane/prostaglandin receptors contribute to high glucose-induced podocyte injury and mitochondrial fission through ROCK1-Drp1 signaling
Increased thromboxane/prostaglandin receptors contribute to high glucose-induced podocyte injury and mitochondrial fission through ROCK1-Drp1 signaling
复制标题
血栓素/前列腺素受体增加通过 ROCK1-Drp1 信号传导导致高糖诱导的足细胞损伤和线粒体裂变
DOI：
10.1016/j.biocel.2022.106281
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发表时间：
2022-08-22
影响因子：
4
通讯作者：
Wang, Cheng
中科院分区：
文献类型：
--
作者：
Liu, Sirui;Li, Xuehong;Wang, Cheng
足细胞线粒体过度分裂是糖尿病肾病（DN）发病机制的中心环节，血栓素/前列腺素受体（TP受体）在DN中起着重要作用。然而，TP受体在足细胞线粒体动力学紊乱中的调节仍然是未知的。在这里，我们首次报道了糖尿病条件下TP受体对足细胞线粒体动力学影响的新机制细节。TP受体的表达显着上调足细胞在糖尿病条件下，在体内和体外。S18886减轻糖尿病小鼠足细胞线粒体分裂、肾小球损伤和肾功能障碍。此外，通过遗传学和药理学方法抑制TP受体，通过调节动力蛋白相关蛋白1（Drp 1）磷酸化及其随后向线粒体的转运，显著减少了线粒体分裂并减轻了高糖诱导的足细胞损伤。相反，TP受体过表达和TP受体激动剂U46619在这些足细胞中的应用表现出对线粒体分裂和足细胞损伤的相反作用。此外，治疗与Y27632，Rho相关激酶1（ROCK 1）的抑制剂，显着钝化更多的碎片线粒体和减少足细胞损伤与TP受体过表达或U46619治疗后的足细胞。最后，药物抑制Drp 1减轻了TP受体过表达足细胞的过度线粒体碎片化和足细胞损伤。我们的数据表明，TP受体的表达增加可以发生在人类培养的足细胞系和来自链脲佐菌素（STZ）诱导的糖尿病小鼠的足细胞，这有助于线粒体过度分裂和足细胞损伤通过ROCK 1-Drp 1信号。
Excessive mitochondrial fission in podocytes serves as a central hub for the pathogenesis of diabetic nephropathy (DN), and the thromboxane/prostaglandin receptor (TP receptor) plays a potential role in DN. However, regu-lation of the TP receptor during mitochondrial dynamics disorder in podocytes remains unknown. Here, we firstly reported novel mechanistic details of TP receptor effects on mitochondrial dynamics in podocytes under diabetic conditions. Expression of the TP receptor was significantly upregulated in podocytes under diabetic conditions both in vivo and in vitro. S18886 attenuated podocyte mitochondrial fission, glomerular injury and renal dysfunction in diabetic mice. Furthermore, inhibition of the TP receptor by both genetic and pharmaco-logical methods dramatically reduced mitochondrial fission and attenuated podocyte injury induced by high glucose through regulating dynamin-related protein 1 (Drp1) phosphorylation and its subsequent translocation to mitochondria. In contrast, TP receptor overexpression and application of TP receptor agonist U46619 in these podocytes showed the opposite effect on mitochondrial fission and podocyte injury. Furthermore, treatment with Y27632, an inhibitor of Rho-associated kinase1 (ROCK1), significantly blunted more fragmented mitochondria and reduced podocyte injuries in podocytes with TP receptor overexpression or after U46619 treatment. Finally, pharmacological inhibition of Drp1 alleviated excessive mitochondrial fragmentation and podocyte damage in TP receptor overexpressing podocytes. Our data suggests that increased expression of the TP receptor can occur in a human cultured podocyte cell line and in podocytes derived from streptozotocin (STZ)-induced diabetic mice, which contributes to mitochondrial excessive fission and podocyte injury via ROCK1-Drp1 signaling.