Cytochrome P450: The Metabolic Pathways and the Genetic/Epigenetic Regulation Involved in Shaping the Story of Diabetic Kidney Disease (DKD).
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Dia, Batoul, American University of Beirut, Beirut, Lebanon
- Shamieh, Elias, American University of Beirut, Beirut, Lebanon
- Azar, Sami, American University of Beirut Medical Center, Beirut, Lebanon
- Eid, Assaad Antoine, American University of Beirut, Beirut, Lebanon
Cytochrome P450 (CYPs) epoxygenases metabolize arachidonic acid (AA) into 20-HETE and EETs. Our group has described the implication of CYPs and their metabolites in the pathogenesis of DKD, in experimental animal model of diabetes. Yet the correlation of these finding in human setting is under investigation. More importantly, CYPs-encoding genes possess polymorphisms that can alter the expression of these key enzymes, affecting the prognosis of patients with DKD. Herein, we hypothesize that alteration in 20-HETE and EETs levels in diabetes leads to kidney injury, and that genetic variants/epigenetic regulation of AA-metabolizing CYPs may potentiate the development of DKD.
Healthy volunteers, individuals diagnosed with type 2 diabetes (T2DM) with or without clinical manifestation of DKD were enrolled in this study. Levels of 20-HETE and EETs were assessed in the urine and plasma samples of the recruited individuals and correlated with the extent of renal injury. To detect single nucleotide polymorphisms (SNPs) in CYP4A11, CYP4F8 and CYP2B6, TaqMan PCR assay was performed on the DNA extracted from the collected blood samples.
Circulating levels of 20-HETE were increased in patients with DKD when compared to T2DM patients with no clinical signs of DKD, which in turn had higher levels of 20-HETE in comparison to the healthy volunteers. This was associated with an increased expression of CYP4A11 and CYP4F8 in the human kidney biopsies of patients with DKD. In parallel, EETs levels were decreased in patients with T2DM and DKD as compared to patients with T2DM only and this was positively correlated with the decreased CYP2B6 expression in kidney biopsies of patients with DKD. Furthermore, a difference in 2 SNPs for CYP2B6 and 1SNP for CYP4A11 was observed across patients with different conditions, suggesting an increased risk with the mutant allele for diabetes and DKD.
This study may yield important findings about novel regulatory pathways involved in diabetes-induced renal injury and may identify novel prognostic/diagnostic biomarkers associated to CYPs pathways in DKD.