Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage.
Epoxyeicosatrienoic acids (EET) have antihypertensive and anti-inflammatory properties and play a role in the maintenance of renal vascular function. A novel approach to increase EET levels is to inhibit epoxide hydrolase enzymes that are responsible for conversion of biologically active EET to dihydroxyeicosatrienoic acids (DHET). We hypothesized that soluble epoxide hydrolase (SEH) inhibition would improve renal vascular function and ameliorate hypertension induced renal damage. Chronic administration of the specific SEH inhibitor 1-cyclohexyl-3-dodecylurea (CDU, 3 mg/d) for 10 d lowered BP in angiotensin hypertensive rats. The contribution of renal vascular SEH to afferent arteriolar function in angiotensin hypertension was also assessed. SEH protein expression was increased in renal microvessels from hypertensive rats. Although CDU did not change afferent arteriolar responsiveness to angiotensin in normotensive animals, CDU treatment significantly attenuated afferent arteriolar diameter responses to angiotensin in hypertensive kidneys from 51% +/- 8% to 28% +/- 7%. Protection of the renal vasculature and glomerulus during chronic CDU administration was demonstrated by histology. Urinary albumin excretion, an index of renal damage, was also lower in CDU-treated hypertensive rats. These data demonstrate that SEH inhibition has antihypertensive and renal vascular protective effects in angiotensin hypertension and suggests that SEH inhibitors may be a useful therapeutic intervention for cardiovascular diseases.
Zhao
Xueying
X
Vascular Biology Center, Department of Physiology, Medical College of Georgia, Augusta, USA.
Yamamoto
Tatsuo
T
Newman
John W
JW
Kim
In-Hae
IH
Watanabe
Takaho
T
Hammock
Bruce D
BD
Stewart
Janet
J
Pollock
Jennifer S
JS
Pollock
David M
DM
Imig
John D
JD
D000804:Angiotensin II; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood; D001160:Arterioles / Q000502:physiology; D001794:Blood Pressure; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006339:Heart Rate; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000201:enzymology / Q000473:pathology*; D019787:Linoleic Acid / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014662:Vasoconstrictor Agents
C450146:1-cyclohexyl-3-dodecylurea; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D016718:Arachidonic Acid; D014508:Urea; D019787:Linoleic Acid; D004851:Epoxide Hydrolases