{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T06:04:27Z","timestamp":1789884267285,"version":"4.0.1"},"reference-count":61,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,1]]},"abstract":"\n Background<\/jats:title>\n During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1\/2 (ERK1\/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1\/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis\u2014mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet\u2014as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1\/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1\/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF-\n \u03b2<\/jats:italic>\n 1, the major profibrotic cytokine, thereby suppressing downstream mTORC1 pathway activation. Additionally, trametinib reduced the expression of myofibroblast marker\n \u03b1<\/jats:italic>\n -smooth muscle actin and the proliferation of renal fibroblasts, corroborating our\n in vivo<\/jats:italic>\n data. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals subsequent to myofibroblast activation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2018020209","type":"journal-article","created":{"date-parts":[[2018,12,10]],"date-time":"2018-12-10T16:25:10Z","timestamp":1544459110000},"page":"33-49","source":"Crossref","is-referenced-by-count":73,"title":["The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1\/2 and mTORC1 Signaling"],"prefix":"10.1681","volume":"30","author":[{"given":"Petros","family":"Andrikopoulos","sequence":"first","affiliation":[{"name":"Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; and"},{"name":"Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Kieswich","sequence":"additional","affiliation":[{"name":"Diabetic Kidney Disease Centre, Renal Unit, Barts Health National Health Service Trust, The Royal London Hospital, London, UK; 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