Abstract: PO0696
CYP450: Protagonists in the Story of Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Dia, Batoul, American University of Beirut, Beirut, Lebanon
- Noureldein, Mohamad, American University of Beirut, Beirut, Lebanon
- Azar, Sami, American University of Beirut, Beirut, Lebanon
- Ziyadeh, Fuad N., American University of Beirut, Beirut, Lebanon
- Eid, Assaad Antoine, American University of Beirut, Beirut, Lebanon
Background
Diabetic kidney disease (DKD) is a grave complication and a major contributor to all-cause mortality in patients with diabetes. Cytochrome P450 (CYPs) epoxygenases metabolize arachidonic acid into the vasoactive and renal-active HETEs and EETs. Our group, among others, advanced the discovery implicating CYPs and their metabolites in the pathogenesis of DKD by regulating reactive oxygen species. Of interest, CYPs-encoding genes possess different polymorphisms which alter the expression of these key enzymes, affecting the prognosis of patients with DKD. Noteworthy, the CYPs polymorphisms and their correlation with the production of 20-HETE and EETs in DKD remain poorly investigated. In the same spirit, extensive research has highlighted the role of different miRNAs in DKD. To our knowledge, the regulatory effect of miRNAs on the expression of different CYPs in DKD is not yet established. In this study, we aim to elucidate the role of CYPs polymorphism, their metabolites, and miRNAs regulating their expression in the disease onset and progression of DKD.
Methods
Blood and urine were collected from patients with type 2 diabetes (T2D) with or without clinical manifestation of DKD. Levels of 20-HETE and EETs were assessed in the urine samples of the patients alongside with the renal CYPs enzymatic activities in human kidney biopsies. Besides, miRNA analysis was performed on the plasma collected from these patients to study CYP enzymes regulation using the Target Scan online tool.
Results
Our data show that the circulating levels of 11,12-EETs were decreased in patients with DKD when compared to T2D patients with no clinical signs of DKD, concomitant with an increase in the 20-HETE levels. Our results show that in patients with DKD, the expression of miRNA was altered ultimately leading to the downregulation of CYP2B6, CYP4A11 and CYP4F8 enzymes. Furthermore, patients with DKD carry CYPs polymorph with the minor allele frequency resulting in an alteration in their enzymatic activity and subsequently increasing 20-HETE and decreasing EETs production concomitant with a positive correlation with the expression of the corresponding CYPs in human kidney biopsies.
Conclusion
This study yields crucial findings about novel genetic and epigenetic pathways involved in DKD and identifies biomarkers related to CYPs pathways that could be of diagnostic, prognostic, and therapeutic value.
Funding
- Private Foundation Support