Abstract
Genes in the epoxygenase pathway of arachidonic acid metabolism leading to vasoactive eicosanoids, mainly 20-hydroxyeicosatetraenoic (20-HETE) and epoxyeicosatrienoic (EETs) acids, have been related to glucose-induced renal damage in preclinical reports. We genotyped 1088 diabetic kidney disease (DKD) patients and controls for seven polymorphisms in five genes (CYP2C8, CYP2J2, CYP4F2, CYP4A11, and EPHX2) along this metabolic route and evaluated their effect on DKD risk, clinical outcomes, and the plasma/urine levels of eicosanoids measured by LC/MS/MS and immunoenzymatic assays. The CYP4F2 433M variant allele was associated with lower incidence of DKD (OR = 0.65 (0.48–0.90), p = 0.008), whilst the CYP2C8*3/*3 genotype was related to increased risk (OR = 3.21 (1.05–9.87), p = 0.036). Patients carrying the 433M allele also showed lower eGFR [median and interquartile range vs. wildtype carriers: 30.8 (19.8) and 33.0 (23.2) mL/min/1.73 m2, p = 0.037). Finally, the 433VM/MM variant genotypes were associated with lower urinary levels of 20-HETE compared with 433VV (3.14 (0.86) vs. 8.45 (3.69) ng/mg Creatinine, p = 0.024). Our results indicate that the CYP4F2 V433M polymorphism, by decreasing 20-HETE levels, may play an important role in DKD.
Highlights
The incidence of chronic kidney disease (CKD) has greatly increased in recent years to become a global healthcare issue
Preclinical reports indicate that these compounds are closely related to the damage induced by hyperglycemia on renal cells [11,12,35,36]
These data support the hypothesis tested in the present work, namely that genetic variants in the arachidonic acid (AA) epoxygenase metabolism may be relevant for diabetic kidney disease (DKD) risk and outcomes
Summary
The incidence of chronic kidney disease (CKD) has greatly increased in recent years to become a global healthcare issue. The greatest contributor to CKD is diabetic kidney disease (DKD), which refers to pathologic structural and functional changes seen in the kidneys of patients with diabetes mellitus (DM). At least 40% of patients with type 2 DM will develop DKD [2], which accounts for over 50% of individuals who require a dialysis treatment and/or renal transplant in some parts of the world [3]. Other indicators include decreased glomerular filtration rate (GFR) or elevated arterial blood pressure [5], which altogether can help the nephrologist to establish a diagnosis that can later be histologically confirmed. It is known that there is a significant proportion of subjects with DKD who, in spite of decreased GFR, do not have elevated concentrations of proteins in urine [6,7]. The necessity of new, universal, and more specific biomarkers of DKD has been repeatedly pointed out [8,9]
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