An association between congestive heart failure (CHF) and chronic kidney disease (CKD) results in extremely poor patient survival rates. Previous studies have shown that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, improves the survival rate in CHF induced by aorto-caval fistula (ACF) and attenuates CKD progression. This prompted us to examine if sEH inhibitor treatment would improve the outcome if both experimental conditions are combined. Fawn-hooded hypertensive (FHH) rats, a genetic model showing early CKD development was employed, and CHF was induced by ACF. Treatment with an sEH inhibitor was initiated 4 weeks after ACF creation, in FHH and in fawn-hooded low-pressure (FHL) rats, a control strain without renal damage. The follow-up period was 20 weeks. We found that ACF FHH rats exhibited substantially lower survival rates (all the animals died by week 14) as compared with the 64% survival rate observed in ACF FHL rats. The former group showed pronounced albuminuria (almost 30-fold higher than in FHL) and reduced intrarenal EET concentrations. The sEH inhibitor treatment improved survival rate and distinctly reduced increases in albuminuria in ACF FHH and in ACF FHL rats, however, all the beneficial actions were more pronounced in the hypertensive strain. These data indicate that pharmacological blockade of sEH could be a novel therapeutic approach for the treatment of CHF, particularly under conditions when it is associated with CKD.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czechia

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czechia

Department of Entomology UCD Cancer Center University of California Davis Davis CA United States

Department of Internal Medicine 1 Cardiology University Hospital Olomouc Palacký University Olomouc Czechia

Department of Pathophysiology 2nd Faculty of Medicine Charles University Prague Czechia

Department of Pharmacology and Toxicology Medical College of Wisconsin Milwaukee WI United States

Department of Physiology Faculty of Science Charles University Prague Czechia

Department of Renal and Body Fluid Physiology Mossakowski Medical Research Centre Polish Academy of Sciences Warsaw Poland

Zobrazit více v PubMed

Abassi Z., Goltsmna I., Karram T., Winaver J., Horrman A. (2011). Aortocaval fistula in rat: a unique model of volume-overload congestive heart failure and cardiac hypertrophy. J. Biomed. Biotechnol. 2011:729497. 10.1155/2011/729497 PubMed DOI PMC

Alánová P., Husková Z., Kopkan L., Sporková A., Jíchová Š., Neckář J., et al. (2015). Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats. Vasc. Pharmacol. 73 45–56. 10.1016/j.vph.2015.08.013 PubMed DOI

Arrigo M., Cippa P. E., Mebazaa A. (2018). Cardiorenal interactions revisited: how to improve heart failure outcomes in patients with chronic kidney disease. Curr. Heart Fail. 10.1007/s11897-018-0406-8 [Epub ahead of print]. PubMed DOI

Benes J., Kazdova L., Drahota Z., Houstek J., Medrikova D., Kopecky J., et al. (2011). Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. Clin. Sci. 121 29–41. 10.1042/CS20100527 PubMed DOI

Benjamin E. J., Blaha M. J., Chiuve S. E., Cushman M., Das S. R., de Ferranti S. D., et al. (2017). Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135 e146–e603. 10.1161/CIR.0000000000000485 PubMed DOI PMC

Braam B., Joles J. A., Daniswar A. H., Gaillard C. A. (2014). Cardiorenal syndrome – current understanding and future perspectives. Nat. Rev. Nephrol. 10 48–55. 10.1038/nrneph.2013.250 PubMed DOI

Braunwald E. (2015). The war against heart failure. Lancet 385 812–824. 10.1016/S0140-6736(14)61889-4 PubMed DOI

Brower G. L., Henegar J. R., Janicki J. S. (1996). Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload. Am. J. Physiol. 40 H2071–H2078. 10.1152/ajpheart.1996.271.5.H2071 PubMed DOI

Brower G. L., Levick S. P., Janicki J. S. (2015). Differential effects of prevention and reversal treatment with lisinopril on left ventricular remodelling in a rat model of heart failure. Heart Lung Circ. 24 919–924. 10.1016/j.hlc.2015.02.023 PubMed DOI PMC

Capdevila J. H., Wang W., Falck J. R. (2015). Arachidonic acid monooxygenase: genetic and biochemical approaches to physiological/pathophysiological relevance. Prostaglandins Other Lipid Mediat. 120 40–49. 10.1016/j.prostaglandins.2015.05.004 PubMed DOI PMC

Čertíková Chábová V., Kujal P., Škaroupková P., Vaňourková Z., Vacková Š., Husková Z., et al. (2018). Combined inhibition of soluble epoxide hydrolase and renin-angiotensin system exhibits superior renoprotection to renin-angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with established chronic kidney disease. Kidney Blood Press Res. 43 329–349. 10.1159/000487902 PubMed DOI PMC

Červenka L., Melenovský V., Husková Z., Škaroupková P., Nishiyama A., Sadowski J. (2015). Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Clin. Exp. Pharmacol. Physiol. 42 795–807. 10.1111/1440-1681.12419 PubMed DOI

Červenka L., Škaroupková P., Kompanowska-Jezierska E., Sadowski J. (2016). Sex-linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula. Clin. Exp. Pharmacol. Physiol. 43 883–895. 10.1111/1440-1681.12619 PubMed DOI

Cohen-Segev R., Francis B., Abu-Saleh N., Awad H., Lazarovich A., Kabala A., et al. (2014). Cardiac and renal distribution of ACE and ACE-2 in rats with heart failure. Acta Histochem. 116 1342–1349. 10.1016/j.acthis.2014.08.006 PubMed DOI

Doleželová Š., Jíchová Š., Husková Z., Vojtíšková A., Kujal P., Hošková L., et al. (2016). Progression of hypertension and kidney disease in aging fawn-hooded rats is mediated by enhanced influence of renin-angiotensin system and suppression of nitric oxide system and epoxyeicosanoids. Clin. Exp. Hypertens. 38 644–651. 10.1080/10641963.2016.1182182 PubMed DOI

Dube P., Weber K. T. (2011). Congestive heart failure: pathophysiologic consequences of neurohormonal activation and the potential for recovery: part I. Am. J. Med. Sci. 342 348–351. 10.1097/MAJ.0b013e318232750d PubMed DOI

Elmarakby A. A. (2012). Reno-protective mechanisms of epoxyeicosatrienoic acids in cardiovascular disease. Am. J. Physiol. 302 R321–R330. 10.1152/ajpregu.00606.2011 PubMed DOI

Fan F., Roman R. J. (2017). Effect of cytochrome P450 metabolites of arachidonic acid in nephrology. J. Am. Soc. Nephrol. 28 2845–2855. 10.1681/ASN.2017030252 PubMed DOI PMC

Fleming I. (2014). The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease. Pharmacol. Rev. 66 1106–1140. 10.1124/pr.113.007781 PubMed DOI

Fox J., Guan S., Hymel A. A., Navar L. G. (1992). Dietary Na and ACE inhibition effects on renal tissue angiotensin I and II and ACE activity in rats. Am J Physiol. 262 F902–F909. 10.1152/ajprenal.1992.262.5.F902 PubMed DOI

Hartupee J., Mann D. L. (2017). Neurohormonal activation in heart failure with reduced ejection fraction. Nat. Rev. Cardiol. 14 30–38. 10.1038/nrcardio.2016.163 PubMed DOI PMC

Hatt P. Y., Rakusan K., Gastineau P., Laplace M., Cluzeaud F. (1980). Aorto-caval fistula in the rat. An experimental model of heart volume overloading. Basic Res. Cardiol. 75 105–108. 10.1007/BF02001401 PubMed DOI

Honetschlagerova Z., Husková Z., Vaňourková Z., Sporková A., Kramer H. J., Hwang S. H., et al. (2011). Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension. J. Physiol. 589 207–219. 10.1113/jphysiol.2010.199505 PubMed DOI PMC

House A. A. (2018). Management of heart failure in advancing CKD: core curriculum 2018. Am. J. Kidney Dis. 72 284–295. 10.1053/j.ajkd.2017.12.006 PubMed DOI

Houser S. R., Margulies K. B., Murphy A. M., Spinale F. G., Francis G. S., Prabhu S. D., et al. (2012). Animal models of heart failure: a scientific statement from the American Heart Association. Circ. Res. 111:e54. 10.1161/RES.0b013e3182582523 PubMed DOI

Husková Z., Kopkan L., Červenková L., Doleželová Š., Vaňourková Z., Škaroupková P., et al. (2016). Intrarenal alterations of the angiotensin-converting type 2/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats. Clin. Exp. Pharmacol. Physiol. 43 438–449. 10.1111/1440-1681.12553 PubMed DOI

Husková Z., Kramer H. J., Thumová M., Vaňourková Z., Burgerová M., Teplan V., et al. (2006a). Effects of anesthesia on plasma and kidney ANG II levels in normotensive and ANG II-dependent hypertensive rats. Kidney Blood Press Res. 29 74–83. PubMed

Husková Z., Kramer H. J., Vaňourková Z., Červenka L. (2006b). Effects of changes in sodium balance on plasma and kidney angiotensin II levels in anesthetized and conscious Ren-2 transgenic rats. J Hypertens. 24 517–522. PubMed

Imig J. D. (2018). Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapies. Pharmacol. Ther. 10.1016/j.pharmthera.2018.06.015 [Epub ahead of print]. PubMed DOI PMC

Jamieson K. L., Endo T., Darwesh A. M., Samokhvalov V., Seubert J. M. (2017). Cytochrome P450-derived eicosanoids and heart function. Pharmacol. Ther. 179 47–83. 10.1016/j.pharmthera.2017.05.005 PubMed DOI

Jha V., Garcia-Garcia G., Iseki K., Li Z., Naicker S., Plattner B., et al. (2013). Chronic kidney disease: global dimension and perspectives. Lancet 382 260–272. 10.1016/S0140-6736(13)60687-X PubMed DOI

Jíchová Š., Doleželová Š., Kopkan L., Kompanowska-Jezierska E., Sadowski J., Červenka L. (2016). Fenefibrate attenuates malignant hypertension by suppression of the renin-angiotensin system: a study in Cyp1a1-Ren-2 transgenic rats. Am. J. Med. Sci. 352 618–630. 10.1016/j.amjms.2016.09.008 PubMed DOI

Kala P., Sedláková L., Škaroupková P., Kopkan L., Vaňourková Z., Táborský M., et al. (2018). Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Physiol. Res. 67 401–415. PubMed PMC

Kobori H., Nishiyama A., Harrison-Bernard L. M., Navar L. G. (2003). Urinary angiotensinogen as an indicator of intrarenal angiotensin status in hypertension. Hypertension 41 42–49. 10.1161/01.HYP.0000050102.90932.CF PubMed DOI PMC

Kobori H., Urushihara M. (2013). Augmented intrarenal and urinary angiotensinogen in hypertension and chronic kidney disease. Pflugers Arch. 465 3–12. 10.1007/s00424-012-1143-6 PubMed DOI PMC

Kopkan L., Husková Z., Sporková A., Varcabová Š., Honetschlagerová Z., Hwan S. H., et al. (2012). Soluble epoxide hydrolase inhibition exhibits antihypertensive actions independently of nitric oxide in mice with renovascular hypertension. Kidney Blood Press Res. 35 595–607. 10.1159/000339883 PubMed DOI PMC

Kujal P., Čertíková Chábová V., Škaroupková P., Husková Z., Vernerová Z., Kramer H. J., et al. (2014). Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats. Clin. Exp. Pharmacol. Physiol. 41 227–237. 10.1111/1440-1681.12204 PubMed DOI PMC

McCune S., Baker P. B., Stills F. H. (1990). SHF/Mcc-cp rat: model of obesity, non-insulin-dependent diabetes, and congestive heart failure. Ilar News 32 23–27. 10.1093/ilar.32.3.23 DOI

Melenovsky V., Cervenka L., Viklicky O., Franekova J., Havlenova T., Behounek M., et al. (2018). Kidney response to heart failure: proteomic analysis of cardiorenal syndrome. Kidney Blood Press Res. 43 1437–1450. 10.1159/000493657 PubMed DOI

Melenovsky V., Skaroupkova P., Benes J., Torresova V., Kopkan L., Cervenka L. (2012). The course of heart failure development and mortality in rats with volume overload due to aorto-caval fistula. Kidney Blood Press Res. 35 167–173. 10.1159/000331562 PubMed DOI

Monti J., Fischer J., Paskas S., Heining M., Schulz H., Gosele C. (2008). Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nat. Genet. 40 529–537. 10.1038/ng.129 PubMed DOI PMC

Mullens W., Verbrugge F. H., Nijst P., Tang W. H. W. (2017). Renal sodium avidity in heart failure: from pathophysiology to treatment strategies. Eur. Heart J. 38 1872–1882. 10.1093/eurheartj/ehx035 PubMed DOI

Oliver-Dussault C., Ascah A., Marcil M., Matas J., Picard S., Pibarot P., et al. (2010). Early predictors of cardiac decompensation in experimental volume overload. Mol. Cell Biochem. 2010 271–281. 10.1007/s11010-009-0361-5 PubMed DOI

Packer M., McMurray J. J. V. (2017). Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure. Lancet 389 1831–1840. 10.1016/S0140-6736(16)30969-2 PubMed DOI

Proovoost A. P. (1994). Spontaneous glomerulosclerosis: insights from the fawn-hooded rat. Kidney Int. Suppl. 45 S2–S5. PubMed

Rivera J., Ward N., Hodgson J., Hodgson J., Puddey I. B., Falck J. R., et al. (2004). Measurement of 20-hydroxyeicosatetraenoic acid in human urine by gas chromatography-mass spectrometry. Clin. Chem. 50 224–226. 10.1373/clinchem.2003.025775 PubMed DOI

Rocic P., Schwartzman M. L. (2018). 20-HETE in the regulation of vascular and cardiac function. Pharmacol. Ther. 192 74–87. 10.1016/j.pharmthera.2018.07.004 PubMed DOI PMC

Roman R. J. (2002). P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev. 82 131–185. 10.1152/physrev.00021.2001 PubMed DOI

Schefold J. C., Filippatos G., Hasenfuss G., Anker S. D., von Haehling S. (2016). Heart failure and kidney dysfunction: epidemiology, mechanisms and management. Nat. Rev. Cardiol. 12 610–623. 10.1038/nrneph.2016.113 PubMed DOI

Sedláková L., Čertíková Chábová V., Doleželová Š., Škaroupková P., Kopkan L., Husková Z., et al. (2017). Renin-angiotensin system blockade alone or combined with ETA receptor blockade: effects on the course of chronic kidney disease in 5/6 nephrectomized Ren-2 transgenic rats. Clin. Exp. Hypertens. 39 183–195. 10.1080/10641963.2016.1235184 PubMed DOI

Sporková A., Jíchová Š., Husková Z., Kopkan L., Nishiyama A., Hwang S. H., et al. (2014). Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: studies in Cyp1a1-Ren-2 transgenic rats. Clin. Exp. Pharmacol. Physiol. 41 1003–1013. 10.1111/1440-1681.12310 PubMed DOI PMC

U.S. Renal Data System (2015). USRDS. Annual Data Report 2015. Seattle, WA: Epidemiology of kidney disease in the United States.

Ziaeian B., Fonarow G. C. (2016). Epidemiology and aetiology of heart failure. Nat. Rev. Cardiol. 13 368–378. 10.1038/nrcardio.2016.25 PubMed DOI PMC

Effects of renal denervation on the course of cardiorenal syndrome: insight from studies with fawn-hooded hypertensive rats

Characterization of a new model of chemotherapy-induced heart failure with reduced ejection fraction and nephrotic syndrome in Ren-2 transgenic rats

Epoxylipids and soluble epoxide hydrolase in heart diseases

Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats

Epoxyeicosatrienoic Acid-Based Therapy Attenuates the Progression of Postischemic Heart Failure in Normotensive Sprague-Dawley but Not in Hypertensive Ren-2 Transgenic Rats