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Macrophage-myofibroblast transition (MMT) contributes to the development of tissue fibrosis. We hypothesized that cellular senescence contributes to MMT and renal fibrosis in mice with renal artery stenosis (RAS). <jats:italic>INK-ATTAC<\/jats:italic> mice expressing <jats:italic>p16<\/jats:italic>\n            <jats:sup>\n              <jats:italic>INK-4a<\/jats:italic>\n            <\/jats:sup> and green fluorescent protein in senescent cells were assigned to control or unilateral RAS, untreated or treated with AP20187 (an apoptosis inducer in <jats:italic>p16<\/jats:italic>\n            <jats:sup>\n              <jats:italic>INK-4a<\/jats:italic>\n            <\/jats:sup>-expressing cells) for 4 weeks. Renal perfusion was studied in vivo using micro-MRI, and kidney morphology, senescence, and MMT ex vivo. Cellular senescence was induced in human renal proximal tubular epithelial cells (HRPTEpiC) in vitro, and interferon-induced transmembrane protein-3 (IFITM3), a cellular senescence vector, was silenced (siRNA) or over-expressed (plasmid). HRPTEpiC were then co-incubated with macrophages with silenced integrin-3 (ITGB3), a regulator of mesenchymal transitions. CD68\/<jats:italic>p16<\/jats:italic>\n            <jats:sup>\n              <jats:italic>INK-4a<\/jats:italic>\n            <\/jats:sup>\/\u03b1-SMA co-expression and senescence markers were studied. Murine RAS kidneys showed increased expression of <jats:italic>p16<\/jats:italic>\n            <jats:sup>\n              <jats:italic>INK-4a<\/jats:italic>\n            <\/jats:sup> and MMT markers (F4\/80, \u03b1-SMA) vs. controls, which decreased after AP20187, as did renal fibrosis and plasma creatinine, whereas renal perfusion increased. IFITM3 and ITGB3 expression were upregulated in senescent HRPTEpiC or co-cultured macrophages, respectively. MMT markers and TGF-\u03b2\/Smad3 expression also rose in these macrophages and decreased after IFITM3 or ITGB3 silencing. <jats:italic>p16<\/jats:italic>\n            <jats:sup>\n              <jats:italic>INK-4a<\/jats:italic>\n            <\/jats:sup>-expressing macrophages may regulate interstitial fibrosis in RAS via MMT. This process is associated with elevated expression of ITGB3 and TGF-\u03b2\/Smad3 pathway activation through neighboring senescent cell-derived IFITM3. These findings may implicate MMT as a therapeutic target in ischemic kidneys.<\/jats:p>","DOI":"10.1038\/s41419-025-07666-1","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T19:06:20Z","timestamp":1746903980000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cellular senescence promotes macrophage-to-myofibroblast transition in chronic ischemic renal disease"],"prefix":"10.1038","volume":"16","author":[{"given":"Yu","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Yang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0287-8496","authenticated-orcid":false,"given":"Wenqi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seo Rin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyra","family":"Jordan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9446-5313","authenticated-orcid":false,"given":"Amir","family":"Lerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Tchkonia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-4905","authenticated-orcid":false,"given":"James L.","family":"Kirkland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3271-3887","authenticated-orcid":false,"given":"Lilach O.","family":"Lerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,10]]},"reference":[{"key":"7666_CR1","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1093\/eurheartj\/ehs197","volume":"34","author":"A Eirin","year":"2013","unstructured":"Eirin A, Gloviczki ML, Tang H, Gossl M, Jordan KL, Woollard JR, et al. 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The other authors declare no conflicts of interest. Dr. Lerman is an advisor to CureSpec, RiboCure, and Cellergy. Drs. Tchkonia and Kirkland have patents and pending patents covering senolytic drugs and their uses that are held by Mayo Clinic.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal studies comply with the Animal Welfare Act (AWA) were approved by the Mayo Clinic Institutional Animal Care and Use Committee (approval no. A00002628-17). All human procedures in compliance with the principles of the Declaration of Helsinki were approved by Zhongda Hospital Affiliated to Southeast University Clinical Research Ethics Committee, and informed consent was obtained from all subjects (approval no. 2023ZDSYLL087-P01).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"372"}}