Induction of Renal 20-Hydroxyeicosatetraenoic Acid by Clofibrate Attenuates High-Fat Diet-Induced Hypertension in Rats

Abstract

This study compared renal hemodynamics, the expression of CYP4A isoforms [the enzymes for 20-hydroxyeicosatetraenoic acid (20-HETE) production], and tubular sodium transporters in male rats fed a high-fat (HF) or control diet for 10 weeks. We also studied the effect of treatment with clofibrate, a CYP4A inducer, on sodium retention and renal function and on CYP4A expression in HF rats. HF rats had higher blood pressure (BP), renal plasma flow, and glomerular filtration rate (GFR), but no significant change in renal vascular resistance. Reverse transcription-polymerase chain reaction analysis showed that CYP4A1 and CYP4A8 expression was significantly decreased in the renal cortex of HF rats. Western blot analysis showed up-regulation of expression of the ␣-subunit of the epithelial sodium channel (␣-ENaC), the ␤-subunit of the epithelial sodium channel (␤-ENaC), sodium/hydrogen exchanger (NHE)-3, and the renal outer medulla K ϩ channel (ROMK) in HF rats, whereas expression of the ␥-subunit of the epithelial sodium channel and the ␣1-subunit of Na ϩ -K ϩ -ATPase remained unchanged. Thus, HF treatment caused the reduction of renal CYP4A1 and CYP4A8 expression, whereas the increases in ␣-ENaC, ␤-ENaC, NHE-3, and ROMK expression in renal tubules may have contributed sodium retention and hypertension in HF rats. Furthermore, clofibrate treatment (240 mg/kg/day) caused the decrease of BP and GFR and the attenuation of cumulative sodium balance in HF rats. The attenuation of sodium retention by clofibrate treatment is linked to decreased expression of NHE-3 in renal cortex. Clofibrate induction of CYP4A expression occurred in proximal tubules and in the thick ascending limb of the loop of Henle but not in renal microvessels. This induction correlated with the expression of peroxisome proliferator-activated receptor (PPAR␣) in renal tubules. Therefore, these results suggest that the effects of clofibrate on sodium retention and blood pressure regulation in HF rats may be due to the induction of renal tubular 20-HETE production through the PPAR␣ pathway.Findings from the 1999 -2000 National Health and Nutrition Examination Survey showed that 59 million adults or 31% of those in the United States are obese. Obesity is an important factor in essential hypertension (Hall, 2003). We have chosen to study rats fed a HF diet because this model mimics the effects of human HF-food consumption. These rats develop characteristic features of human obesity-induced hypertension such as increased sodium balance, renal tubular reabsorption, and glomerular filtration rate (Dobrian et al., 2000;Hall, 2003).20-Hydroxyeicosatetraenoic acid (20-HETE) is a major metabolite of arachidonic acid in the rat kidneys; its synthesis and actions have been localized primarily to the microcirculation and renal tubules (Roman, 2002). 20-HETE synthesis is catalyzed primarily by CYP4A isoforms (Roman, 2002 ABBREVIATIONS: HF, high fat; HETE, 20-hydroxyeicosatetraenoic acid; TALH, thick ascending limb of the loop of Henle; ROMK, renal outer medulla K...

Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats

“…The downregulation of renal tubular EET production is associated with hypertension, abnormal renal hemodynamics, and sodium retention (41). To substantiate these findings, we postulated that the increased production of EETs by fenofibrate and AUDA can affect blood pressure, renal hemodynamics, and sodium retention in HF rats.…”

“…MAP, RBF, and RVR measurements were obtained from a computerized data collection-and-analysis system (EMKA Technologies, Falls Church, VA). A fluorescent plate reader (GENios Plus, Tecan, Research Triangle Park, NC) at 485-nm excitation and 538-nm emission was used to determine the concentration of FITC-inulin in plasma and urine for calculation of GFR, as described previously (23,41).…”

“…We have chosen this model because it mimics the effects of human HF-food consumption; rats develop characteristic features of human obesity-induced hypertension, including increased renal tubular reabsorption and glomerular filtration rate (GFR) (8). Moreover, the increased blood pressure in HF rats is associated with sodium retention (41), decreased expression of renal CYP epoxygenase, and decreased production of renal EETs (33,42).…”

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

“…Reduction of mean arterial pressure and plasma IL-6 by fenofibrate in an acute model of DOCA-salt hypertension suggested a crosstalk relationship between PPARα and IL-6 in regulating blood pressure [22] . Increased renal tubular 20-HETE production with a natriuretic effect for PPARα has also been proposed in regulation of blood pressure in DOCA-salt-treated mice [23] .…”

Evaluation of CMV and KAP promoters for driving the expression of human CYP4F2 in transgenic mice

“…One is prohypertension resulting from constriction of the small arteries (4,5). The other is anti-hypertension caused by inhibition of sodium reabsorption (6,7). We have previously elucidated the prohypertensive action of 20-HETE derived from CYP4F2 in the human population and in a transgenic mouse model (8,9).…”