Antioxidant enzyme peroxiredoxin 5 regulates cyst growth and ciliogenesis via modulating Plk1 stability.
Antioxidant enzyme peroxiredoxin 5 regulates cyst growth and ciliogenesis via modulating Plk1 stability.
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DOI：
10.1096/fj.202101270rr
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发表时间：
2022-01
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氧化应激正在成为囊性疾病中促进体内平衡的一个因素。然而，抗氧化酶在常染色体显性多囊肾病（ADPKD）发病机制中的作用尚不清楚。过氧化氧还蛋白5 （peroxredoxin 5, Prdx5）是一种催化H2O2和烷基过氧化氢还原的抗氧化酶，在不同的生物过程中发挥重要作用。在这项研究中，我们发现Prdx5在PKD突变小鼠模型和ADPKD患者肾脏中下调。Prdx5的敲低导致三维小鼠IMCD细胞Matrigel培养系统中形成囊肿。Prdx5缺乏介导囊肿生长的机制包括：1)诱导氧化应激，其表现为氧化应激标志物血红素氧化酶-1 (HO-1) mRNA表达增加；2)激活Erk、S6和mTORC1，参与囊肾上皮细胞增殖和囊肿生长；3)中心体扩增异常和多极纺锤体形成导致基因组不稳定；4) polo样激酶1 （Plk1）和极光激酶A （AurA）的上调，这是参与细胞增殖和纤毛发生的重要有丝分裂激酶；5)小鼠IMCD3和视网膜色素上皮细胞（RPE）初级纤毛形成受损，可通过抑制Plk1活性来挽救；6)抑制Wnt3a和Wnt5a配体对小鼠IMCD3细胞原代纤毛的作用，同时分别通过单独的纤毛独立机制调节典型和非典型Wnt信号的活性。重要的是，我们发现靶向Plk1及其抑制剂volasertib可以延迟Pkd1条件敲除小鼠肾脏的囊肿生长。总之，这些发现表明Prdx5是一种重要的抗氧化剂，通过多种机制调节囊肿生长，特别是Prdx5-Plk1轴，并且诱导和激活Prdx5，单独或联合抑制Plk1，代表了对抗ADPKD的有希望的策略。
Oxidative stress is emerging as a contributing factor to the homeostasis in cystic diseases. However, the role of antioxidant enzymes plays in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) remains elusive. Peroxiredoxin 5 (Prdx5) is an antioxidant enzyme that catalyzes the reduction of H2O2 and alkyl hydroperoxide and plays an important role in different biological processes. In this study, we show that Prdx5 is downregulated in a PKD mutant mouse model and ADPKD patient kidneys. Knockdown of Prdx5 resulted in the formation of cysts in a three-dimensional mouse IMCD cell Matrigel culture system. The mechanisms of Prdx5 deficiency mediated cyst growth include: 1) induction of oxidative stress as indicated by increased mRNA expression of heme oxygenase-1 (HO-1), an oxidant stress marker; 2) activation of Erk, S6 and mTORC1, which contribute to cystic renal epithelial cell proliferation and cyst growth; 3) abnormal centrosome amplification and multipolar spindle formation which result in genome instability; 4) upregulation of Polo-like kinase 1 (Plk1) and Aurora kinase A (AurA), important mitotic kinases involved in cell proliferation and ciliogenesis; 5) impaired formation of primary cilia in mouse IMCD3 and retinal pigment epithelial (RPE) cells, which could be rescued by inhibiting Plk1 activity; and 6) restraining the effect of Wnt3a and Wnt5a ligands on primary cilia in mouse IMCD3 cells, while regulating the activity of the canonical and non-canonical Wnt signaling in a separate cilia independent mechanism, respectively. Importantly, we found that targeting Plk1 with its inhibitor, volasertib, delayed cyst growth in Pkd1 conditional knockout mouse kidneys. Together, these findings indicate that Prdx5 is an important antioxidant that regulates cyst growth via diverse mechanisms, in particular, the Prdx5-Plk1 axis, and that induction and activation of Prdx5, alone or together with inhibition of Plk1, represent a promising strategy for combatting ADPKD.
T细胞因子/β-catenin活性在两种不同的常染色体显性多囊肾脏疾病中抑制。
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19.6
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