Abstract-Dietary lipids are reported to affect the blood pressure in both humans and experimental animal models with hypertension. In the present study, 2-kidney, 1-clip (2K1C) hypertensive rats were treated with the modified fatty acid tetradecylthioacetic acid (TTA) from the time of clipping or after hypertension was established. TTA treatment attenuated the development of hypertension and reduced established 2K1C hypertension. The mRNA level of renin in the clipped kidney and the plasma renin activity were markedly reduced, and the plasma angiotensin II level tended to decrease after TTA treatment. In addition, TTA reduced the mRNA level of angiotensinogen in white adipose tissue.Prevention of organ damage was demonstrated by normal urinary excretion of protein, maintained serum albumin, lower heart weight, and clearly reduced vascular, glomerular, and tubulointerstitial damage in the nonclipped kidney. Renal function was not affected as estimated by unchanged plasma creatinine. Furthermore, the serum levels of triacylglycerol and cholesterol were reduced by TTA. The serum fatty acid composition was changed, resulting in a favorable increase of oleic acid. However, the levels of all of the omega-3 fatty acids and of linoleic acid were reduced, and no change was seen in the level of arachidonic acid, but the urinary excretion of 8-iso-prostaglandin F2␣ was declined. In conclusion, TTA attenuated the development of hypertension, reduced established hypertension, and prevented the development of organ damage in 2K1C rats, possibly by reducing the amounts of the vasoconstrictors angiotensin II and 8-iso-prostaglandin F2␣ and by inducing a favorable increase of oleic acid in serum. Key Words: renin-angiotensin system Ⅲ renal disease Ⅲ fatty acids E levated blood pressure is closely related to increase in cardiovascular death from events like stroke, myocardial infarction, and chronic renal failure 1 and is defined as one of the risk factors for the metabolic syndrome. 2,3 Other risk factors include insulin resistance, hyperglycemia, and elevated serum triacylglycerol, which are conditions that are improved in rats after treatment with the modified fatty acid tetradecylthioacetic acid (TTA). 4 The pleiotropic effects of TTA seem to be mediated through both peroxisome proliferator-activated receptor (PPAR)-dependent and PPAR-independent mechanism 4 and include changes in the fatty acid composition of both liver and serum in rats. [5][6][7] Based on these potential possibilities to change composition of the metabolic system, and because the fatty acid composition of cholesteryl ester and phospholipids in serum has been related to the blood pressure level in humans, 8 -10 we examined the effect of TTA on hypertension in the present study.An inducible model of high blood pressure is the 2-kidney, 1-clip (2K1C) hypertension model, where the increased blood pressure is induced after clipping of one renal artery. This is an angiotensin II-dependent model of hypertension with increased level of plasma renin and angioten...

1R) level in the nonclipped kidney of twokidney, one-clip hypertension (2K1C) has shown to be unchanged despite a high circulating angiotensin (ANG) II level. To examine the vasoreactive response to ANG II in this kidney, injections of ANG II into renal artery were performed 6 wk after clipping of the kidney and compared with normotensive controls. The renal blood flow (RBF) response to 2.5 ng ANG II was measured by a Transonic transit-time flowmeter, before and after indomethacin and candesartan treatment, and analyzed by a computer program. The RBF response to 5 ng arginine-vasopressin (AVP) was examined for comparison with ANG II. The mRNA for AT 1A and AT1B as well as Western blotting for AT 1R in renal resistance vessels were determined, and plasma renin activity (PRA) was measured. Systolic blood pressure was 183 Ϯ 4 mmHg in 2K1C rats compared with 113 Ϯ 1 mmHg in controls (P Ͻ 0.001). PRA was significantly increased in 2K1C animals (P Ͻ 0.05). Injection of ANG II reduced RBF with 10 Ϯ 2% in the nonclipped kidney and 24 Ϯ 3% in controls (P Ͻ 0.001). After indomethacin, the RBF response increased from 10 Ϯ 2 to 20 Ϯ 3% (P Ͻ 0.02) in 2K1C rats and from 24 Ϯ 3 to 34 Ϯ 6% in controls (P Ͻ 0.01). The doses of candesartan needed to completely inhibit RBF response to ANG II were 30 g/kg in the nonclipped kidney and 100 g/kg in controls (P Ͻ 0.001). Western blotting and mRNA for AT 1A and AT1B in the nonclipped kidney were similar to the controls. The results indicate that despite no difference in total AT 1R levels, functional AT1R is downregulated in the nonclipped kidney of 2K1C rats. plasma renin activity; AT 1 receptor; renal blood flow; blood pressure TWO-KIDNEY, ONE-CLIP (2K1C) hypertension is an angiotensin II (ANG II)-dependent model of hypertension, and plasma as well as intrarenal ANG II concentrations are increased (14, 15). Removal of the clip is followed by rapid reversal of high blood pressure with normalization of renin values (14, 15). ANG II mediates its effect in the renal vasculature through two main G-coupled receptors, the AT 1 (AT 1 R) and AT 2 receptors, where AT 1 R mediates the vascular constrictor effects of ANG II (2). The rat has two types of AT 1 receptors, the AT 1A and AT 1B receptors (AT 1A and AT 1B ), which have 95% homology in their receptor amino acid sequences (16). The AT 2 receptor has only 34% homology with the AT 1 R and is expressed at a low level, particularly in the renal vasculature (7).The AT 1A receptor plays an essential role in the development of 2K1C hypertension, as knockout mice lacking this receptor do not develop hypertension (3). Usually AT 1A is downregulated when the ANG II levels are high, as during a low-salt diet, and upregulated when ANG II levels are low, as in high salt intake (25). In the nonclipped kidney, reports indicate that the modulation of the AT 1 R is different from controls and this seems also to be the case during long-term infusion of ANG II (13). The data concerning regulation of the AT 1 R in the nonclipped kidney are, however, contro...

ANG II promotes inflammation through nuclear factor-kappaB (NF-kappaB)-mediated induction of cytokines and reactive oxygen species (ROS). The aim of the present study was to examine the effect of tetradecylthioacetic acid (TTA), a modified fatty acid, on NF-kappaB, proinflammatory markers, ROS, and nitric oxide (NO) production in two-kidney, one-clip (2K1C) hypertension. The 2K1C TTA-treated group had lower blood pressure (128 +/- 3 mmHg) compared with 2K1C nontreated (178 +/- 5 mmHg, P < 0.001). The p50 and p65 subunits of NF-kappaB were higher in the clipped kidney (0.44 +/- 0.01 and 0.22 +/- 0.01, respectively) compared with controls (0.25 +/- 0.03 and 0.12 +/- 0.02, respectively, P < 0.001). In the 2K1C TTA-treated group, these values were similar to control levels. The same pattern of response was seen in the nonclipped kidney. In 2K1C hypertension, cytokines plasma were higher than in control: TNF-alpha was 13.5 +/- 2 pg/ml (P < 0.03), IL-1beta was 58.8 +/- 10 pg/ml (P = 0.003), IL-6 was 210 +/- 33 pg/ml (P < 0.001), and monocyte chemoattractant protein-1 was 429 +/- 21 pg/ml (P = 0.04). In the 2K1C TTA-treated group, these values were similar to controls, and the same pattern was seen in the clipped kidney. Clipping increased 8-iso-PGF-2alpha (P < 0.01) and decreased NO production (P < 0.01 vs. control) in the urine. TTA treatment normalized these values. NO production was also lower in clipped and nonclipped kidney (P < 0.001). After TTA treatment, these values were similar to controls. The results indicate that TTA has a potent anti-inflammatory effect in 2K1C by inhibition of p50/p65 NF-kappaB subunit activation, reduction of cytokines production and ROS, and enhanced NO production.

Bivol LM, Berge RK, Iversen BM. Differential effect of tetradecythioacetic acid on the renin-angiotensin system and blood pressure in SHR and 2-kidney, 1-clip hypertension. Am J Physiol Renal Physiol 293: F839-F845, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00140.2007.-The tetradecythioacetic acid (TTA) is a modified fatty acid known to exhibit pleiotropic effects. First, we compared the effect of TTA on the blood pressure in spontaneously hypertensive rats (SHR) with two-kidney, one-clip (2K1C)-hypertensive rats. Second, we examined mechanisms involved in the blood pressure reduction. TTA had minor effect on systolic blood pressure (SBP) in young SHR up to 8 wk of age. In 2K1C we confirmed the blood pressure-lowering effect of TTA (SBP: 173 Ϯ 4 before vs. 138 Ϯ 3 mmHg after TTA, P Ͻ 0.001). No effect on SBP was seen in Wistar-Kyoto rat (WKY) controls. Plasma renin activity (PRA) was low in SHR and WKY controls and TTA did not change it. PRA decreased from 22.9 Ϯ 1.3 to 16.2 Ϯ 2.2 ng ⅐ ml Ϫ1 ⅐ h Ϫ1 (P ϭ 0.02) in 2K1C. Plasma ANG II concentration declined from 101 Ϯ 3 to 81 Ϯ 5 fmol/l after TTA treatment (P ϭ 0.005). In the clipped kidney, tissue ANG I concentration decreased from 933 Ϯ 68 to 518 Ϯ 60 fmol/g tissue (P ϭ 0.001), and ANG II decreased from 527 Ϯ 38 to 149 Ϯ 21 fmol/g tissue (P Ͻ 0.001) after TTA treatment. In the nonclipped kidney, TTA did not change ANG I and moderately reduced ANG II levels. The renal blood flow response to injection of ANG II into the nonclipped kidney was blunted compared with controls and normalized with TTA treatment (10 Ϯ 2 before vs. 20 Ϯ 2%, P Ͻ 0.001). The results indicate that TTA downregulates the renin-angiotensin system in high renin animals but has no effect in low renin models. Angiotensin I; angiotensin II HYPERTENSION IS CLOSELY related to an increase in cardiovascular death and represents a major challenge in health care all over the world. The use of animal models has been of major importance in examining the mechanisms involved in the development and maintenance of high blood pressure and is widely used in studies of new antihypertensive drugs to explore the mechanisms involved in blood pressure reduction.Several rat models are used. The spontaneously hypertensive rat (SHR) is a genetic model of hypertension and is looked upon as a model for essential hypertension in humans (32). In this model, the activity of the renin-angiotensin system is normal or low (27). Despite this, the commonly used ACE inhibitor and AT1 receptor blockers lower blood pressure in SHR (16,29).The 2-kidney, 1-clip (2K1C) is a renovascular model of hypertension with increased activity of renin-angiotensin system that plays a key role in the development and maintenance of high blood pressure (17, 21). The plasma renin and ANG II concentrations are high for several weeks after clipping, a finding that may be due to increased ANG II production and/or decreased ANG II degradation (17,19). The renin concentration, as well as the levels of ANG I and II, is high in the clipped ki...