Development of gene silencer pyrrole-imidazole polyamides targeting GSK3β for treatment of polycystic kidney diseases.
Development of gene silencer pyrrole-imidazole polyamides targeting GSK3β for treatment of polycystic kidney diseases.
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开发针对 GSK3β 的基因沉默剂吡咯-咪唑聚酰胺用于治疗多囊肾病。
DOI：
10.1016/j.jphs.2023.01.001
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Abe M.
中科院分区：
文献类型：
--
作者：
Baba S;Fukuda N;Kobayashi H;Tsunemi A;Akiya Y;Matsumoto T;Abe M.
环磷酸腺苷（cAMP）-反应元件结合蛋白（CREB）-糖原合成酶激酶3β（GSK 3 β）信号通路参与了常染色体显性多囊肾病（ADPKD）的发病过程。我们设计并合成了吡咯-咪唑（PI）聚酰胺作为新型的基因沉默剂，以阻止CREB与GSK 3 β基因启动子的结合，并研究了PI聚酰胺对小鼠集合管M1细胞增殖和包囊形成的影响。GSK 3 β PI聚酰胺可明显抑制Forskolin诱导的M1细胞GSK 3 βmRNA的表达。为了获得ADPKD的集合管细胞，用shRNA敲除PKD 1基因。低浓度的forskolin显著促进PKD 1基因敲除的M1细胞的增殖，而GSK 3 β PI聚酰胺显著抑制PKD 1基因敲除的M1细胞的增殖。用毛喉素刺激5天诱导PKD 1敲低的M1细胞的囊肿扩大。在PKD 1基因敲减的M1细胞中，GSK 3 β PI聚酰胺显著抑制forskolin刺激的囊肿扩大。因此，本研究表明，PI聚酰胺靶向CREB结合的GSK 3 β基因的转录抑制抑制PKD 1敲低的M1细胞的增殖和包囊形成。GSK 3 β PI聚酰胺可能成为治疗ADPKD的新药物。
The cyclic adenosine monophosphate (cAMP)–response element binding protein (CREB)–glycogen synthase kinase 3β (GSK3β) signaling pathway was reported to be involved in the progression of autosomal dominant polycystic kidney diseases (ADPKD). We designed and synthesized pyrrole-imidazole (PI) polyamides as novel gene-silencers to prevent binding of CREB on the GSK3β gene promoter and examined the effects of the PI polyamides on proliferation and cyst formation of mouse collecting duct M1 cells. The GSK3β PI polyamides significantly inhibited expression ofGSK3βmRNA in M1 cells with forskolin. To obtain cells as collecting ducts from ADPKD, thePKD1gene was knocked down by shRNA. Lower concentrations of forskolin significantly stimulated proliferation ofPKD1knock-down M1 cells, whereas GSK3β PI polyamide significantly inhibited proliferation ofPKD1knock-down M1 cells with forskolin. Stimulation with forskolin for 5 days induced enlargement of cysts fromPKD1knock-down M1 cells. GSK3β PI polyamides significantly suppressed the enlargement of cysts with forskolin stimulation inPKD1knock-down M1 cells. Thus, the present study showed that transcriptional suppression of theGSK3βgene by PI polyamides targeting the binding of CREB inhibited the proliferation and cyst formation ofPKD1knock-down M1 cells. The GSK3β PI polyamides may potentially be novel medicines for ADPKD.
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影响因子：
13.6
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通讯作者：
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作者：
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通讯作者：
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