Notch3信号和CREB/KLF15通路在调节阿霉素肾病肾小球壁上皮细胞表型改变中的拮抗相互作用

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Yuqing Zhu , Kaili Chang , Ke Sun , Yifeng Wang , Zhonghua Zhao , Qi Chen , Qiaojing Qin , Xueguang Liu
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引用次数: 0

摘要

排列在鲍曼囊内的壁上皮细胞(PECs)被认为是足细胞的祖细胞,在损伤后表现出有限的再生能力。Notch3受体已被发现在局灶节段性肾小球硬化(FSGS)的足细胞和PECs中共同表达,提示在这种情况下具有独特的调节作用。我们之前的研究表明,在阿霉素(ADR)损伤足细胞中,Notch3信号通路与cAMP-PKA-CREB-KLF15通路呈显著负相关。鉴于PECs和足细胞的共同胚胎起源,我们假设Notch3信号和CREB-KLF15通路可能在PECs的表型改变中起关键作用。我们制造了Notch3敲除小鼠,并建立了adr诱导的肾病。值得注意的是,Notch3敲低可改善中年小鼠(56-60周)和adr肾病小鼠的肾功能和形态学。在Notch3+/−小鼠中,PECs共表达足细胞标记物的数量明显高于野生型小鼠。在培养的PECs中,ADR通过调节Notch3信号通路和CREB-KLF15通路直接诱导PECs表型改变。慢病毒转染过表达Notch3导致PECs显著活化,p-ERK表达增加。此外,cAMP-PKA通路的选择性激活剂pCPT-cAMP或VRAD培养基显著增强了CREB-KLF15通路和足细胞标志物的表达。MEK/ERK特异性抑制剂U0126显著抑制Notch3信号通路,同时增加CREB-KLF15的表达。综上所述,这些发现表明Notch3-p-ERK信号和CREB-KLF15信号通路在调节PECs表型中发挥拮抗作用,p-ERK可能在这两个信号通路之间的相互作用中起着分子开关的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Antagonistic interaction between Notch3 signaling and CREB/KLF15 pathway in regulating the phenotypic alterations of glomerular parietal epithelial cells in adriamycin-induced nephropathy
Parietal epithelial cells (PECs) that line the Bowman’s capsule are considered progenitor cells for podocytes, which exhibit limited regeneration capacity following injury. Notch3 receptor has been found to be co-expressed in both podocytes and PECs in focal segmental glomerulosclerosis (FSGS), suggesting a distinct regulatory role in this context. Our previous research indicated that Notch3 signaling is significantly negatively correlated with the cAMP-PKA-CREB-KLF15 pathway in adriamycin (ADR)-injured podocytes. Given the common embryonic origin of PECs and podocytes, we hypothesize that Notch3 signaling and CREB-KLF15 pathway may play a critical role in the phenotypic alterations of PECs. We generated Notch3 knockout mice and established ADR-induced nephropathy. Notably, Notch3 knockdown improved both renal function and morphology in middle-aged mice (56–60 weeks) and those with ADR-induced nephropathy. In Notch3+/− mice, the number of PECs co-expressing podocyte markers was significantly higher compared to that in wild-type mice. In cultured PECs, ADR directly induced phenotypic changes of PECs by modulating Notch3 signaling and CREB-KLF15 pathway. Notch3 overexpression by lentiviral transfection resulted in significant activation of PECs and increased expressions of p-ERK. Furthermore, pCPT-cAMP, a selective activator of cAMP-PKA pathway, or VRAD medium, markedly enhanced CREB-KLF15 pathway and the expressions of podocyte markers. U0126, a specific inhibitor of MEK/ERK, significantly inhibited Notch3 signaling while concurrently increasing the expression of CREB-KLF15. Taken together, these findings suggest that Notch3-p-ERK signaling and CREB-KLF15 pathway exert antagonistic effects in modulating PECs phenotype, with p-ERK potentially serving as a molecular switch in the interaction between these two signaling pathways.
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
期刊介绍: Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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