Effect of Subtotal Renal Nephrectomy on CYP450-Mediated Metabolism of Arachidonic Acid: A Potential Player in Pathogenesis of Renocardiac Syndrome?
- *Corresponding Author:
- Kingma JG
Institut Universitaire de Cardiologie et de Pneumologie de Québec
2725, Chemin Sainte-Foy, Québec City, Qc G1V 4G5, Canada
Fax: 418 656-4509
E-mail: [email protected]
Received Date: September 02, 2016; Accepted Date: September 27, 2016; Published Date: October 03, 2016
Citation: Kingma JG, Rouleau JR, Patoine D, Pilote S, Drolet B, et al. (2016) Effect of Subtotal Renal Nephrectomy on CYP450-Mediated Metabolism of Arachidonic Acid: A Potential Player in Pathogenesis of Renocardiac Syndrome? Cardiovasc Pharm Open Access 5:197. doi: 10.4172/2329-6607.1000197
Copyright: © 2016 Kingma JG, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background/Aims: Cardiovascular events are common in patients with renocardiac syndrome. A direct link between endothelial dysfunction and increased cardiovascular events has not been established for this syndrome; however, a causal role could be attributed to modulations of Cytochrome P450-mediated (CYP450) eicosanoid metabolites including Epoxyeicosatrienoic (EETs), Dihydroxyeicosatrienoic (DHET) and 20-Hydroxyeicosatetraenoic acids (20-HETE). In this study we investigated inter-organ variations in CYP450-mediated eicosanoids in key organs from dogs with renal insufficiency.
Methods: Renal insufficiency was induced by two-stage subtotal nephrectomy (SNx). Biochemical markers (serum creatinine, blood urea nitrogen) and cardiac hemodynamics were measured weekly. After 5 weeks, arachidonic acid CYP450-metabolites in heart, remnant kidney and liver biopsies were analyzed.
Results: Serum creatinine and blood urea nitrogen were significantly higher in the SNx group (versus timematched sham controls); hematocrit, body weight and creatinine clearance were significantly reduced. The lymphocyte:monocyte ratio, a biomarker of vascular risk, was lower (p=NS) in SNx dogs. Cardiac hemodynamics were similar for both groups. Cardiac levels of 20-HETE were markedly lower (p=0.014) in SNx dogs; however, 14, 15-DHET, a biomarker of soluble epoxide hydrolase levels were unchanged. The 20-HETE/14, 15-DHET ratio was lower in these dogs (p=0.003) and could help to explain a loss of autoregulation in this experimental model. In kidney and liver biopsies from SNx dogs 20-HETE tended to be higher and 14, 15-DHET lower (p=NS) versus time-matched controls; no change was observed for 20-HETE/14, 15-DHET.
Conclusion: A marked reduction of cardiac 20-HETE and 20-HETE/14, 15-DHET levels occurred in dogs with kidney injury but no change in these CYP450-metabolites was observed in kidney or liver biopsies. As such, kidney injury appears to trigger significant alterations in CYP450-metabolites that may initiate endothelial dysfunction and vascular inflammation even in distant organs. Manipulating these pathways may eventually constitute a potential pharmacologic target to limit vessel dysfunction in the setting of renocardiac syndrome.