Please use this identifier to cite or link to this item: https://scholarhub.balamand.edu.lb/handle/uob/6892
Title: VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease
Authors: Njeim, Rachel
Braych, Kawthar
Ghadieh, Hilda 
Azar, Nadim S.
Azar, William S.
Dia, Batoul
Leone, Angelo
Cappello, Francesco
Kfoury, Hala
Harb, Frederic 
Jurjus, Abdo R.
Eid, Assaad A.
Ziyadeh, Fuad N.
Affiliations: Faculty of Medicine 
Issue Date: 2023-01-20
Publisher: National Library of Medicine
Part of: Diabetes
Volume: 72
Issue: 7
Start page: 947
End page: 957
Abstract: 
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 cyto-chrome P450 2C (CYP2C)–derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-do-decanoic acid (AUDA) in drinking water for 6 weeks. In par-allel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti–VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were eu-thanized, 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 vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hy-perglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, fol-lowed by the activation of VEGF-A signaling and upregula-tion 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.
URI: https://scholarhub.balamand.edu.lb/handle/uob/6892
ISSN: 00121797
DOI: 10.2337/db22-0636
Type: Journal Article
Appears in Collections:Faculty of Medicine

Show full item record

Google ScholarTM

Check

Altmetric

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.