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Madrid","award":["RD21\/0005\/0002"],"award-info":[{"award-number":["RD21\/0005\/0002"]}]},{"name":"INNOREN, Comunidad de Madrid","award":["RD24\/0004\/0001"],"award-info":[{"award-number":["RD24\/0004\/0001"]}]},{"name":"INNOREN, Comunidad de Madrid","award":["PID2023-147378OB-I00"],"award-info":[{"award-number":["PID2023-147378OB-I00"]}]},{"name":"INNOREN, Comunidad de Madrid","award":["CD23\/00049"],"award-info":[{"award-number":["CD23\/00049"]}]},{"name":"INNOREN, Comunidad de Madrid","award":["CP23\/00025"],"award-info":[{"award-number":["CP23\/00025"]}]},{"name":"INNOREN, Comunidad de Madrid","award":["PIPF-2023\/SAL-GL-29648"],"award-info":[{"award-number":["PIPF-2023\/SAL-GL-29648"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence. In response to kidney damage, cellular senescence mechanisms are activated, linked to regeneration failure and progression to fibrosis. Our preclinical studies using a total conditional CCN2 knockout mouse demonstrate that CCN2 plays a significant role in the development of a senescence phenotype after exposure to a nephrotoxic agent. CCN2 induces cell growth arrest in TECs, both in the early phase and in the chronic phase of folic acid nephropathy (FAN), associated with cell-death\/necroinflammation and fibrosis, respectively. Renal CCN2 overexpression was found to be linked to excessive collagen accumulation in tubulointerstitial areas, microvascular rarefaction, and a decline in renal function, which were observed three weeks following the initial injury. All these findings were markedly diminished in conditional CCN2 knockout mice. In the FAN model, injured senescent TECs are associated with microvascular rarefaction, and both were modulated by CCN2. In primary cultured endothelial cells, as previously described in TECs, CCN2 directly induced senescence. The findings collectively demonstrate the complexity of CCN2, highlight the pivotal role of cellular senescence as an important mechanism in renal injury, and underscore the critical function of this biomolecule in kidney damage progression.<\/jats:p>","DOI":"10.3390\/ijms26094401","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T05:54:43Z","timestamp":1746510883000},"page":"4401","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CCN2 Activates Cellular Senescence Leading to Kidney Fibrosis in Folic Acid-Induced Experimental Nephropathy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4295-7284","authenticated-orcid":false,"given":"Lucia","family":"Tejedor-Santamaria","sequence":"first","affiliation":[{"name":"Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma Madrid, 28040 Madrid, Spain"},{"name":"Instituto de Salud Carlos III., 28029 Madrid, Spain"}]},{"given":"Laura","family":"Marquez-Exposito","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma Madrid, 28040 Madrid, Spain"},{"name":"Instituto de Salud Carlos III., 28029 Madrid, Spain"}]},{"given":"Alicia","family":"Villacampa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Universidad Aut\u00f3noma de Madrid, 28029 Madrid, Spain"},{"name":"Vascular Pharmacology and Metabolism (FARMAVASM) Group, IdiPAZ, 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-0229","authenticated-orcid":false,"given":"Vanessa","family":"Marchant","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma Madrid, 28040 Madrid, Spain"},{"name":"Instituto de Salud Carlos III., 28029 Madrid, Spain"}]},{"given":"Antonio","family":"Battaglia-Vieni","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma Madrid, 28040 Madrid, Spain"}]},{"given":"Sandra","family":"Rayego-Mateos","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma Madrid, 28040 Madrid, Spain"},{"name":"Instituto de Salud Carlos III., 28029 Madrid, Spain"}]},{"given":"Raul R.","family":"Rodrigues-Diez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Medicine, Complutense University, 28040 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-1504","authenticated-orcid":false,"given":"Fatima Milhano","family":"Santos","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Biology in Renal and Vascular Pathology, Department of Medicine, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma Madrid, 28040 Madrid, Spain"},{"name":"Instituto de Salud Carlos III., 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3676-6596","authenticated-orcid":false,"given":"Floris A.","family":"Valentijn","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}]},{"given":"Sebastian N.","family":"Knoppert","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX Utrecht, The 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