Abstract
Objectives: Cardiovascular diseases (CVD) remain the leading cause of morbimortality in patients with chronic kidney disease (CKD). The aim of this study was to assess the cardiovascular impact of the pharmacological inhibition of soluble epoxide hydrolase (sEH), which metabolizes the endothelium-derived vasodilatory and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acid (DHETs), in the 5/6 nephrectomy (Nx) mouse model. Methods and Results: Compared to sham-operated mice, there was decrease in EET-to-DHET ratio 3 months after surgery in vehicle-treated Nx mice but not in mice treated with the sEH inhibitor t-AUCB. Nx induced an increase in plasma creatinine and in urine albumin-to-creatinine ratio as well as the development of kidney histological lesions, all of which were not modified by t-AUCB. In addition, t-AUCB did not oppose Nx-induced blood pressure increase. However, t-AUCB prevented the development of cardiac hypertrophy and fibrosis induced by Nx, as well as normalized the echocardiographic indices of diastolic and systolic function. Moreover, the reduction in endothelium-dependent flow-mediated dilatation of isolated mesenteric arteries induced by Nx was blunted by t-AUCB without change in endothelium-independent dilatation to sodium nitroprusside. Conclusion: Inhibition of sEH reduces the cardiac remodelling, and the diastolic and systolic dysfunctions associated with CKD. These beneficial effects may be mediated by the prevention of endothelial dysfunction, independent from kidney preservation and antihypertensor effect. Thus, inhibition of sEH holds a therapeutic potential in preventing type 4 cardiorenal syndrome.
Highlights
Chronic kidney disease (CKD) is an important health care problem with a worldwide prevalence around 13% (Hill et al, 2016)
Several studies have shown that higher levels of fibroblast growth factor-23 (FGF-23) are associated with a higher risk of death (Scialla et al, 2014; Charytan et al, 2015).In spite of significant breakthroughs in our understanding and treatment of the CV disease associated with CKD, mortality remains high and identifying new therapeutic targets is of critical importance
Body weight increased in sham-operated mice from surgery to sacrifice but not in 5/6 Nx mice treated with either vehicle or trans-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]-benzoic acid (t-AUCB) (Figure 1B), without significant change in survival between groups. (Figure 1C)
Summary
Chronic kidney disease (CKD) is an important health care problem with a worldwide prevalence around 13% (Hill et al, 2016). CKD is an independent risk factor for cardiovascular (CV) diseases and CV events are the first cause of death in this population (Hatamizadeh et al, 2013). Cardiorenal Syndrome and Epoxyeicosatrienoic Acids cardiopathy or type 4 cardiorenal syndrome (Zannad Faiez and Rossignol Patrick, 2018). In this setting, the crosstalk between the diseased kidney and heart is not fully understood. Several studies have shown that higher levels of FGF-23 are associated with a higher risk of death (Scialla et al, 2014; Charytan et al, 2015).In spite of significant breakthroughs in our understanding and treatment of the CV disease associated with CKD, mortality remains high and identifying new therapeutic targets is of critical importance
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
