Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE

Kazuyoshi Inoue, Komal Sodhi, Nitin Puri, Katherine H. Gotlinger, Jiang Cao, Rita Rezzani, John R. Falck, Nader G. Abraham, Michal Laniado-Schwartzman

Research output: Contribution to journalArticle

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Abstract

We have previously reported that adenoviral-mediated delivery of cytochrome P-450 (CYP) 4A2, which catalyzes the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), results in endothelial dysfunction and hypertension in Sprague-Dawley (SD) rats (Wang JS, Singh H, Zhang F, Ishizuka T, Deng H, Kemp R, Wolin MS, Hintze TH, Abraham NG, Nasjletti A, Laniado-Schwartzman M. Circ Res 98: 962-969, 2006). In this study, we targeted the vascular endothelium by using a lentivirus construct expressing CYP4A2 under the control of the endothelium-specific promoter VE-cadherin (VECAD-4A2) and examined the effect of long-term CYP4A2 overexpression on blood pressure and kidney function in SD rats. A bolus injection of VECAD-4A2 increased blood pressure (P < 0.001) by 26, 36, and 30 mmHg 10, 20, and 30 days postinjection, respectively. Arteries from VECAD-4A2-transduced rats produced increased levels of 20-HETE (P < 0.01), expressed lower levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p-eNOS) (P < 0.05), generated higher levels of superoxide anion, and displayed decreased relaxing responsiveness to acetylcholine (P < 0.05). Proteinuria increased by twofold in VECAD-4A2-transduced rats compared with controls. Treatment of VECAD-4A2-transduced rats with HET0016, an inhibitor of 20-HETE biosynthesis, not only attenuated the increase in blood pressure (P < 0.05) but also improved vascular function (acetylcholine-induced relaxations) and reduced plasma creatinine and proteinuria. HET0016 treatment decreased oxidative stress and increased the phosphorylated state of key proteins that regulate endothelial function, including eNOS, AKT, and AMPK. Collectively, these findings demonstrate that augmentation of vascular endothelial 20-HETE levels results in hypertension, endothelial dysfunction, and renal injury, which is offset by HET0016 through a reduction in vascular 20-HETE coupled with a lessening of oxidative stress and the amplification of pAKT, pAMPK, and p-eNOS levels leading to normalization of endothelial responses.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number4
DOIs
StatePublished - Oct 2009

Fingerprint

Renal Hypertension
Nitric Oxide Synthase Type III
Wounds and Injuries
Blood Vessels
Blood Pressure
Proteinuria
Acetylcholine
Sprague Dawley Rats
Oxidative Stress
Hypertension
Kidney
Lentivirus
AMP-Activated Protein Kinases
Vascular Endothelium
Superoxides
Cytochrome P-450 Enzyme System
Endothelium
Creatinine
Arteries
cytochrome P-450 CYP4A2 (rat)

Keywords

  • Cyp4a-derived 20-HETE
  • Endothelial dysfunction
  • Endothelial-specific promoter
  • Lentiviral vectors
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE. / Inoue, Kazuyoshi; Sodhi, Komal; Puri, Nitin; Gotlinger, Katherine H.; Cao, Jiang; Rezzani, Rita; Falck, John R.; Abraham, Nader G.; Laniado-Schwartzman, Michal.

In: American Journal of Physiology - Renal Physiology, Vol. 297, No. 4, 10.2009.

Research output: Contribution to journalArticle

Inoue, Kazuyoshi ; Sodhi, Komal ; Puri, Nitin ; Gotlinger, Katherine H. ; Cao, Jiang ; Rezzani, Rita ; Falck, John R. ; Abraham, Nader G. ; Laniado-Schwartzman, Michal. / Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE. In: American Journal of Physiology - Renal Physiology. 2009 ; Vol. 297, No. 4.
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AU - Cao, Jiang

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