{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T10:19:16Z","timestamp":1780395556422,"version":"3.54.1"},"reference-count":49,"publisher":"American Diabetes Association","issue":"7","license":[{"start":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T00:00:00Z","timestamp":1674172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Predoctoral scholarship from the American University of Beirut"},{"name":"A Medical Practice Plan (MPP) regular research grant from the American University of Beirut"},{"name":"National Council for Scientific Research"},{"name":"Qatar National Research Foundation","award":["National Priority Research Program regular researc"],"award-info":[{"award-number":["National Priority Research Program regular researc"]}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,7,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)\u2013derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg\/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti\u2013VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in\u00a0vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n                  <jats:p>Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)\u2013derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes\u2013induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db22-0636","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T18:04:50Z","timestamp":1674237890000},"page":"947-957","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":17,"title":["VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease"],"prefix":"10.2337","volume":"72","author":[{"given":"Rachel","family":"Njeim","sequence":"first","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"},{"name":"2AUB Diabetes, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kawthar","family":"Braych","sequence":"additional","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda E.","family":"Ghadieh","sequence":"additional","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"},{"name":"2AUB Diabetes, American University of Beirut, Beirut, Lebanon"},{"name":"3Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Koura, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadim S.","family":"Azar","sequence":"additional","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"},{"name":"2AUB Diabetes, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S.","family":"Azar","sequence":"additional","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"},{"name":"2AUB Diabetes, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Batoul","family":"Dia","sequence":"additional","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"},{"name":"2AUB Diabetes, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Leone","sequence":"additional","affiliation":[{"name":"4Department of Biomedicine, Neurosciences and Advanced Diagnosis, School of Medicine, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cappello","sequence":"additional","affiliation":[{"name":"4Department of Biomedicine, Neurosciences and Advanced Diagnosis, School of Medicine, University of Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"Kfoury","sequence":"additional","affiliation":[{"name":"5Department of Pathology and Laboratory Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Harb","sequence":"additional","affiliation":[{"name":"3Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Koura, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdo R.","family":"Jurjus","sequence":"additional","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3603-0960","authenticated-orcid":false,"given":"Assaad A.","family":"Eid","sequence":"additional","affiliation":[{"name":"1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon"},{"name":"2AUB Diabetes, American University of Beirut, Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuad N.","family":"Ziyadeh","sequence":"additional","affiliation":[{"name":"6Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, 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