Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats

Petr Kujal, Vera Čertíková Chábová, Petra Škaroupková, Zuzana Husková, Zdena Vernerová, Herbert J. Kramer, Agnieszka Walkowska, Elzbieta Kompanowska-Jezierska, Janusz Sadowski, Kento Kitada, Akira Nishiyama, Sung H. Hwang, Bruce D. Hammock, John D. Imig, L. Červenka

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Summary: The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II-dependent hypertension. Soluble epoxide hydrolase was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. When applied in TGR subjected to 5/6 NX, c-AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ-protective actions were associated with normalization of the intrarenal EETs : DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII-dependent hypertension, and that restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions.

Original languageEnglish (US)
Pages (from-to)227-237
Number of pages11
JournalClinical and Experimental Pharmacology and Physiology
Volume41
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Transgenic Rats
Epoxide Hydrolases
Chronic Renal Insufficiency
Acids
Sprague Dawley Rats
Hypertension
Kidney
Benzoic Acid
Cardiomegaly
Transgenes
Proteinuria
Angiotensin II
Drinking Water
Blood Pressure
Wounds and Injuries

Keywords

  • 5/6 nephrectomy
  • Chronic kidney disease
  • Cytochrome P450 enzymes
  • End-organ damage
  • Epoxyeicosatrienoic acids
  • Hypertension
  • Renin-angiotensin system
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Pharmacology

Cite this

Kujal, P., Čertíková Chábová, V., Škaroupková, P., Husková, Z., Vernerová, Z., Kramer, H. J., ... Červenka, L. (2014). Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats. Clinical and Experimental Pharmacology and Physiology, 41(3), 227-237. https://doi.org/10.1111/1440-1681.12204

Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats. / Kujal, Petr; Čertíková Chábová, Vera; Škaroupková, Petra; Husková, Zuzana; Vernerová, Zdena; Kramer, Herbert J.; Walkowska, Agnieszka; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz; Kitada, Kento; Nishiyama, Akira; Hwang, Sung H.; Hammock, Bruce D.; Imig, John D.; Červenka, L.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 41, No. 3, 2014, p. 227-237.

Research output: Contribution to journalArticle

Kujal, P, Čertíková Chábová, V, Škaroupková, P, Husková, Z, Vernerová, Z, Kramer, HJ, Walkowska, A, Kompanowska-Jezierska, E, Sadowski, J, Kitada, K, Nishiyama, A, Hwang, SH, Hammock, BD, Imig, JD & Červenka, L 2014, 'Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats', Clinical and Experimental Pharmacology and Physiology, vol. 41, no. 3, pp. 227-237. https://doi.org/10.1111/1440-1681.12204
Kujal, Petr ; Čertíková Chábová, Vera ; Škaroupková, Petra ; Husková, Zuzana ; Vernerová, Zdena ; Kramer, Herbert J. ; Walkowska, Agnieszka ; Kompanowska-Jezierska, Elzbieta ; Sadowski, Janusz ; Kitada, Kento ; Nishiyama, Akira ; Hwang, Sung H. ; Hammock, Bruce D. ; Imig, John D. ; Červenka, L. / Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats. In: Clinical and Experimental Pharmacology and Physiology. 2014 ; Vol. 41, No. 3. pp. 227-237.
@article{1b2fae85d84543298a71d99a7b54b0ba,
title = "Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats",
abstract = "Summary: The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II-dependent hypertension. Soluble epoxide hydrolase was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. When applied in TGR subjected to 5/6 NX, c-AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ-protective actions were associated with normalization of the intrarenal EETs : DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII-dependent hypertension, and that restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions.",
keywords = "5/6 nephrectomy, Chronic kidney disease, Cytochrome P450 enzymes, End-organ damage, Epoxyeicosatrienoic acids, Hypertension, Renin-angiotensin system, Soluble epoxide hydrolase",
author = "Petr Kujal and {Čert{\'i}kov{\'a} Ch{\'a}bov{\'a}}, Vera and Petra Škaroupkov{\'a} and Zuzana Huskov{\'a} and Zdena Vernerov{\'a} and Kramer, {Herbert J.} and Agnieszka Walkowska and Elzbieta Kompanowska-Jezierska and Janusz Sadowski and Kento Kitada and Akira Nishiyama and Hwang, {Sung H.} and Hammock, {Bruce D.} and Imig, {John D.} and L. Červenka",
year = "2014",
doi = "10.1111/1440-1681.12204",
language = "English (US)",
volume = "41",
pages = "227--237",
journal = "Clinical and Experimental Pharmacology and Physiology",
issn = "0305-1870",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats

AU - Kujal, Petr

AU - Čertíková Chábová, Vera

AU - Škaroupková, Petra

AU - Husková, Zuzana

AU - Vernerová, Zdena

AU - Kramer, Herbert J.

AU - Walkowska, Agnieszka

AU - Kompanowska-Jezierska, Elzbieta

AU - Sadowski, Janusz

AU - Kitada, Kento

AU - Nishiyama, Akira

AU - Hwang, Sung H.

AU - Hammock, Bruce D.

AU - Imig, John D.

AU - Červenka, L.

PY - 2014

Y1 - 2014

N2 - Summary: The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II-dependent hypertension. Soluble epoxide hydrolase was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. When applied in TGR subjected to 5/6 NX, c-AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ-protective actions were associated with normalization of the intrarenal EETs : DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII-dependent hypertension, and that restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions.

AB - Summary: The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II-dependent hypertension. Soluble epoxide hydrolase was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. When applied in TGR subjected to 5/6 NX, c-AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ-protective actions were associated with normalization of the intrarenal EETs : DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII-dependent hypertension, and that restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions.

KW - 5/6 nephrectomy

KW - Chronic kidney disease

KW - Cytochrome P450 enzymes

KW - End-organ damage

KW - Epoxyeicosatrienoic acids

KW - Hypertension

KW - Renin-angiotensin system

KW - Soluble epoxide hydrolase

UR - http://www.scopus.com/inward/record.url?scp=84896322811&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896322811&partnerID=8YFLogxK

U2 - 10.1111/1440-1681.12204

DO - 10.1111/1440-1681.12204

M3 - Article

C2 - 24471737

AN - SCOPUS:84896322811

VL - 41

SP - 227

EP - 237

JO - Clinical and Experimental Pharmacology and Physiology

JF - Clinical and Experimental Pharmacology and Physiology

SN - 0305-1870

IS - 3

ER -