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The receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, has been implicated in disease pathogenesis. In mice subjected to unilateral ureteral obstruction\u2013induced (UUO-induced) or adenine diet\u2013induced (AD-induced) renal fibrosis, models of progressive kidney fibrosis, we demonstrate increased kidney expression of RIPK3. Mice genetically deficient in RIPK3 displayed decreased kidney fibrosis and improved kidney function relative to WT mice when challenged with UUO or AD. In contrast, mice genetically deficient in mixed-lineage kinase domain-like protein (MLKL), a downstream RIPK3 target, were not protected from UUO-induced kidney fibrosis. We demonstrate a pathway by which RIPK3 promotes fibrogenesis through the AKT-dependent activation of ATP citrate lyase (ACL). Genetic or chemical inhibition of RIPK3 suppressed the phosphorylation of AKT and ACL in response to TGF-\u03b21 in fibroblasts. Inhibition of AKT or ACL suppressed TGF-\u03b21\u2013dependent extracellular matrix production and myofibroblast differentiation in fibroblasts. Pharmacological inhibition of ACL suppressed UUO-induced kidney fibrosis. RIPK3 expression was highly regulated in human CKD kidney. In conclusion, we identify a pathway by which RIPK3 promotes kidney fibrosis independently of MLKL-dependent necroptosis as a promising therapeutic target in CKD.<\/jats:p>","DOI":"10.1172\/jci.insight.94979","type":"journal-article","created":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T11:01:03Z","timestamp":1518001263000},"source":"Crossref","is-referenced-by-count":108,"title":["RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase"],"prefix":"10.1172","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2813-4102","authenticated-orcid":true,"given":"Mitsuru","family":"Imamura","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. 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