20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

Yan Ding, Cheng Chia Wu, Victor Garcia, Irina Dimitrova, Adam Weidenhammer, Gregory Joseph, Frank Zhang, Vijay L. Manthati, J R Falck, Jorge H. Capdevila, Michal L. Schwartzman

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20- HEDE) prevented 5α-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14-/- mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 ±1 vs. 15 ± 1 μm) and M/L (0.29±0.03 vs. 0.17±0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12-20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 ± 4 vs. 92 ± 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 ±1 vs. 16 ± 1 μm; M/L: 0.39 ±0.04 vs. 0.23 ± 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels.

Original languageEnglish (US)
Pages (from-to)F753-F763
JournalAmerican Journal of Physiology - Renal Physiology
Volume305
Issue number5
DOIs
StatePublished - Sep 1 2013

Keywords

  • 20-hydroxyeicosatetraenoic acid
  • Androgen
  • Blood pressure
  • Cytochrome P-450 4A

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Ding, Y., Wu, C. C., Garcia, V., Dimitrova, I., Weidenhammer, A., Joseph, G., Zhang, F., Manthati, V. L., Falck, J. R., Capdevila, J. H., & Schwartzman, M. L. (2013). 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension. American Journal of Physiology - Renal Physiology, 305(5), F753-F763. https://doi.org/10.1152/ajprenal.00292.2013