{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:21:01Z","timestamp":1788448861767,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T00:00:00Z","timestamp":1692230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AHA Postdoc Fellowship Award","award":["834582"],"award-info":[{"award-number":["834582"]}]},{"name":"AHA Postdoc Fellowship Award","award":["1R01DK126763-01"],"award-info":[{"award-number":["1R01DK126763-01"]}]},{"name":"National Institute of Diabetes and Digestive and kidney Diseases","award":["834582"],"award-info":[{"award-number":["834582"]}]},{"name":"National Institute of Diabetes and Digestive and kidney Diseases","award":["1R01DK126763-01"],"award-info":[{"award-number":["1R01DK126763-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Renal fibrosis, a hallmark of chronic kidney diseases, is driven by the activation of renal fibroblasts. Recent studies have highlighted the role of glycolysis in this process. Nevertheless, one critical glycolytic activator, 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase 3 (PFKFB3), remains unexplored in renal fibrosis. Upon reanalyzing the single-cell sequencing data from Dr. Humphreys\u2019 lab, we noticed an upregulation of glycolysis, gluconeogenesis, and the TGF\u03b2 signaling pathway in myofibroblasts from fibrotic kidneys after unilateral ureter obstruction (UUO) or kidney ischemia\/reperfusion. Furthermore, our experiments showed significant induction of PFKFB3 in mouse kidneys following UUO or kidney ischemia\/reperfusion. To delve deeper into the role of PFKFB3, we generated mice with Pfkfb3 deficiency, specifically in myofibroblasts (Pfkfb3f\/f\/PostnMCM). Following UUO or kidney ischemia\/reperfusion, a substantial decrease in fibrosis in the injured kidneys of Pfkfb3f\/f\/PostnMCM mice was identified compared to their wild-type littermates. Additionally, in cultured renal fibroblast NRK-49F cells, PFKFB3 was elevated upon exposure to TGF\u03b21, accompanied by an increase in \u03b1-SMA and fibronectin. Notably, this upregulation was significantly diminished with PFKFB3 knockdown, correlated with glycolysis suppression. Mechanistically, the glycolytic metabolite lactate promoted the fibrotic activation of NRK-49F cells. In conclusion, our study demonstrates the critical role of PFKFB3 in driving fibroblast activation and subsequent renal fibrosis.<\/jats:p>","DOI":"10.3390\/cells12162081","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T10:15:48Z","timestamp":1692267348000},"page":"2081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["PFKFB3-Mediated Glycolysis Boosts Fibroblast Activation and Subsequent Kidney Fibrosis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5582-3771","authenticated-orcid":false,"given":"Qiuhua","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Augusta Preparatory Day School, 285 Flowing Wells Rd, Martinez, GA 30907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhidan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Dong","sequence":"additional","affiliation":[{"name":"Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7450-2589","authenticated-orcid":false,"given":"John M.","family":"Asara","sequence":"additional","affiliation":[{"name":"Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1692-2451","authenticated-orcid":false,"given":"Qingqing","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1056\/NEJMra1300575","article-title":"Fibrosis\u2014A common pathway to organ injury and failure","volume":"372","author":"Rockey","year":"2015","journal-title":"N. 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