Yuqing Zhu , Kaili Chang , Ke Sun , Yifeng Wang , Zhonghua Zhao , Qi Chen , Qiaojing Qin , Xueguang Liu
{"title":"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","authors":"Yuqing Zhu , Kaili Chang , Ke Sun , Yifeng Wang , Zhonghua Zhao , Qi Chen , Qiaojing Qin , Xueguang Liu","doi":"10.1016/j.yexcr.2025.114724","DOIUrl":null,"url":null,"abstract":"<div><div>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<sup>+/−</sup> 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.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"451 2","pages":"Article 114724"},"PeriodicalIF":3.5000,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Antagonistic interaction between Notch3 signaling and CREB/KLF15 pathway in regulating the phenotypic alterations of glomerular parietal epithelial cells in adriamycin-induced nephropathy\",\"authors\":\"Yuqing Zhu , Kaili Chang , Ke Sun , Yifeng Wang , Zhonghua Zhao , Qi Chen , Qiaojing Qin , Xueguang Liu\",\"doi\":\"10.1016/j.yexcr.2025.114724\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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<sup>+/−</sup> 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.</div></div>\",\"PeriodicalId\":12227,\"journal\":{\"name\":\"Experimental cell research\",\"volume\":\"451 2\",\"pages\":\"Article 114724\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental cell research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014482725003246\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental cell research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014482725003246","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
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.
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.