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Council","doi-asserted-by":"publisher","award":["202008230182"],"award-info":[{"award-number":["202008230182"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"name":"J.A.M.","award":["R01DK098141"],"award-info":[{"award-number":["R01DK098141"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic kidney disease (CKD) is characterized by proximal tubule (PT) stress, oxidative injury, and metabolic dysfunction. Human kidney single-nucleus RNA sequencing (snRNA-seq) identified enrichment of ubiquitin-dependent protein catabolic processes in injured PT cells, suggesting activation of the ubiquitin-proteasome system during tubular stress. Because Cullin 3 (CUL3), scaffold of ubiquitin ligases, regulates oxidative stress signaling through the KEAP1 (Kelch-like ECH-associated protein 1)\u2013NRF2 (nuclear factor erythroid 2-related factor 2) axis, we investigated its role in PT injury and stress adaptation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human CKD snRNA-seq data and kidney immunostaining were used to define PT cell states, CUL3-associated pathways, and CUL3 localization. Injury-associated CUL3 regulation was examined in wild-type mice after ischemia-reperfusion injury (IRI). Inducible PT-specific knockout mice (Slc34a1-CreER; Cul3flox\/flox) were analyzed at baseline and after injury by histology, immunostaining, proteomics, and injury assessment. In addition, proteomic analysis of a whole-tubule epithelial knockout model (Pax8-rtTA\/LC1; Cul3flox\/flox) was performed. In immortalized human PT cells, CUL3 was suppressed or activated using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) interference and CRISPR activation, followed by bulk RNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CUL3 transcript and protein expression was enriched in stressed PT states in human CKD. In mice, CUL3 protein abundance increased after injury, supporting injury-associated induction in vivo. PT-specific CUL3 deletion increased antioxidant NQO1 (NAD(P)H quinone dehydrogenase 1) expression without causing overt baseline injury. Proteomic analysis of isolated CUL3-deficient PT cells revealed induction of antioxidant, detoxification, proteostasis, and lipid metabolic programs, together with suppression of mitochondrial oxidative metabolism. Similar changes were observed in whole-tubule Cul3 knockout model. In gene-edited human PT cells, CUL3 suppression recapitulated stress-associated and metabolic remodeling programs, whereas CUL3 activation induced reciprocal transcriptional changes. Despite induction of antioxidant pathways, PT-specific CUL3 deletion did not alter disease severity after IRI or aristolochic acid nephropathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CUL3 is an injury-induced regulator of PT metabolic and stress-associated states and modulates antioxidant defense and mitochondrial metabolism in PT cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ndt\/gfag202","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:47:26Z","timestamp":1788353246000},"source":"Crossref","is-referenced-by-count":0,"title":["Cullin 3 ubiquitin ligase regulates redox defense and metabolic programs in proximal tubule 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