8-11-14-eicosatrienoic-acid and Hypertension--Renal

Since epoxyeicosatrienoic acids (EETs) affect sodium reabsorption in renal tubules and dilate the renal vasculature, we have examined their effects on renal hemodynamics and sodium balance in male rats fed a high-fat (HF) diet by fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist and an inducer of cytochrome P-450 (CYP) epoxygenases; by N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH), a selective EET biosynthesis inhibitor; and by 12-(3-adamantane-1-yl-ureido)dodecanoic acid (AUDA), a selective inhibitor of soluble epoxide hydrolase. In rats treated with fenofibrate (30 mg.kg(-1).day(-1) ig) or AUDA (50 mg/l in drinking water) for 2 wk, mean arterial pressure, renal vascular resistance, and glomerular filtration rate were lower but renal blood flow was higher than in vehicle-treated control rats. In addition, fenofibrate and AUDA decreased cumulative sodium balance in the HF rats. Treatment with MSPPOH (20 mg.kg(-1).day(-1) iv) + fenofibrate for 2 wk reversed renal hemodynamics and sodium balance to the levels in control HF rats. Moreover, fenofibrate caused a threefold increase in renal cortical CYP epoxygenase activity, whereas the fenofibrate-induced elevation of this activity was attenuated by MSPPOH. Western blot analysis showed that fenofibrate induced the expression of CYP epoxygenases in renal cortex and microvessels and that the induction effect of fenofibrate was blocked by MSPPOH. These results demonstrate that the fenofibrate-induced increase of CYP epoxygenase expression and the AUDA-induced stabilization of EET production in the kidneys cause renal vascular dilation and reduce sodium retention, contributing to the improvement of abnormal renal hemodynamics and hypertension in HF rats.

Topics: 8,11,14-Eicosatrienoic Acid; Adamantane; Animals; Blood Pressure; Blotting, Western; Diet; Dietary Fats; Fenofibrate; Glomerular Filtration Rate; Hypertension, Renal; Hypolipidemic Agents; Immunohistochemistry; Kidney; Lauric Acids; Male; Obesity; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium; Vascular Resistance; Water-Electrolyte Balance

Interest in the modulation of renal diseases by polyunsaturated fatty acids (PUFA) led this group to examine the effects of borage oil (BO) and corn oil (CO) in the rat 5/6-renal-ablation model. BO is a rich source of gamma-linolenic acid (GLA; 18:3n-6), which is elongated to dihomogamma-linolenic acid (DGLA; 20:3n-6). CO is a rich source of linoleic acid (LA; 18:2n-6), a GLA and arachidonic acid (AA; 20:4n-6) precursor. The purpose of this study was to assess whether an increased DGLA:AA ratio as provided by BO would confer benefits beyond those provided by LA present in corn oil. Forty rats were used for the experiment. Seven rats were used for presurgery measurements. The remaining animals were subjected to 5/6 nephrectomy. Surviving rats (N = 30) were fed regular laboratory diet (RLD) for 7 days, at which time seven rats were used to obtain 1-wk postnephrectomy data. The remainder were then allocated to receive either RLD (N = 8), 15% BO (N = 8), or 15% CO (N = 7) diets for 20 wk. Body weight, renal phospholipid levels, renal function (proteinuria and GFR), glomerular histology, glomerular macrophage infiltration, urinary prostaglandin levels (thromboxane B2 (TxB2), 6-keto-PGF1 alpha), plasma lipid levels, and blood pressure were measured. Diets were well tolerated by all groups with a similar age-related gain in weight throughout the study. Efficacy of the PUFA diets was confirmed by alteration in renal tissue phospholipids; LA decreased in the RLD and BO groups, but not in the CO group. AA was higher in the BO and CO rats, but only the BO group showed a rise in GLA and DGLA incorporation. Proteinuria increased progressively in the RLD group but remained at 1-wk postsurgery levels in the BO and CO groups. Decline in GFR and mesangial expansion were significantly lessened by BO supplementation only. Both PUFA diets limited glomerulosclerosis and macrophage infiltration, but direct comparisons between BO and CO groups revealed significantly less glomerulosclerosis and macrophage infiltration in the BO group. Both BO and CO attenuated the rise in the TxB2 excretion rate and restored the 6-keto-PGF1 alpha:TxB2 ratio to the 1-wk postsurgery level. Plasma lipid levels rose in all groups, but the rise in cholesterol level was less in the BO and CO rats, CO being the most efficacious in this regard. BP increased progressively in RLD rats, but not in the BO and CO groups, BO providing a markedly greater hypotensive effect. In summary, both CO and BO supplemen

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Body Weight; Corn Oil; Dietary Fats, Unsaturated; gamma-Linolenic Acid; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Kidney; Lipids; Macrophages; Male; Nephrectomy; Phospholipids; Plant Oils; Rats; Rats, Sprague-Dawley