Abstract-The present study tested the hypothesis that increasing epoxyeicosatrienoic acids by inhibition of soluble epoxide hydrolase (sEH) would lower blood pressure and ameliorate renal damage in salt-sensitive hypertension. Rats were infused with angiotensin and fed a normal-salt diet or an 8% NaCl diet for 14 days. The sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), was given orally to angiotensin-infused animals during the 14-day period. Plasma AUDA metabolite levels were measured, and they averaged 10Ϯ2 ng/mL in normal-salt angiotensin hypertension and 19Ϯ3 ng/mL in high-salt angiotensin hypertension on day 14 in the animals administered the sEH inhibitor. Mean arterial blood pressure averaged 161Ϯ4 mm Hg in normal-salt and 172Ϯ5 mm Hg in the high-salt angiotensin hypertension groups on day 14. EH inhibitor treatment significantly lowered blood pressure to 140Ϯ5 mm Hg in the normal-salt angiotensin hypertension group and to 151Ϯ6 mm Hg in the high-salt angiotensin hypertension group on day 14. The lower arterial blood pressures in the AUDA-treated groups were associated with increased urinary epoxide-to-diol ratios. Urinary microalbumin levels were measured, and ED-1 staining was used to determine renal damage and macrophage infiltration in the groups. Two weeks of AUDA treatment decreased urinary microalbumin excretion in the normal-salt and high-salt angiotensin hypertension groups and macrophage number in the high-salt angiotensin hypertension group. These data demonstrate that sEH inhibition lowers blood pressure and ameliorates renal damage in angiotensin-dependent, salt-sensitive hypertension. Key Words: kidney Ⅲ inflammation Ⅲ endothelium-derived factors Ⅲ albuminuria A lthough treatment of hypertension has significantly advanced in recent decades, a chronic elevation in blood pressure still results in progressive renal damage, as evidenced by the escalating incidence of end-stage renal disease (ESRD). 1,2 The development of hypertension after long-term administration of angiotensin has many of the same renal and vascular changes that are associated with human essential hypertension. 3,4 Likewise, animal models of angiotensindependent hypertension demonstrate a further elevation in blood pressure when fed a high-salt diet or salt sensitivity. [3][4][5] High dietary salt also increases the susceptibility to kidney damage in hypertensive patients and in angiotensindependent hypertensive rats. 3,4 These parallels between patients with essential hypertension and the angiotensin infusion model make this an extremely useful model to evaluate early changes that occur in the kidney that ultimately result in ESRD.Cytochrome P450 epoxygenase metabolites are involved in the long-term regulation of blood pressure and in the response of the kidney to a high-salt diet. 6 -8 Similarly, salt-sensitive hypertension is associated with an inability of the kidney to properly increase epoxygenase levels. 8 -10 Recent studies have provided evidence that increasing epoxygenase levels have renal-and c...

The present study tested the hypothesis that altered vascular regulation of arachidonic acid enzymes in obese Zucker rats contributes to renal damage. Protein expression of CYP450 (cytochrome P450) and COX (cyclo-oxygenase) enzymes in renal microvessels was studied in obese and lean Zucker rats at 20-21 weeks of age. Body weight and blood glucose averaged 649+/-13 g and 142+/-10 mg/dl in obese Zucker rats compared with 437+/-10 g and 111+/-5 mg/dl in age-matched lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased and CYP2C protein levels decreased in obese Zucker rats. TX (thromboxane) B2 excretion was 2-fold higher and PG (prostaglandin) E2 excretion significantly lower in obese Zucker rats. Additional studies investigated the ability of the COX-2 inhibitor, rofecoxib, to slow the progression of renal injury in obese Zucker rats. Rofecoxib treatment decreased urinary PGF2alpha and 8-isoprostane levels in obese Zucker rats. Renal microvessel mRNA expression of pro-inflammatory chemokines was decreased in COX-2-inhibitor-treated obese Zucker rats. Urinary albumin excretion, an index of kidney damage, averaged 95+/-11 mg/day in vehicle-treated and 9+/-1 mg/day in rofecoxib-treated obese Zucker rats. Glomerulosclerosis, characterized by mesangial expansion, tubulo-interstitial fibrosis and extracellular matrix accumulation, was prominent in obese Zucker rats compared with a lack of damage in age-matched lean Zucker rats and rofecoxib-treated obese Zucker rats. These results suggest that altered vascular arachidonic acid enzymes contribute to the renal damage, and that COX-2 inhibition decreases glomerular injury in obese Zucker rats.