Peroxisome Proliferator-Activated Receptor-α Activation Reduces Salt-Dependent Hypertension During Chronic Endothelin B Receptor Blockade

Abstract

Abstract-Endothelin B (ET B ) receptor stimulation inhibits sodium transport in a similar fashion as 20-HETE. Clofibrate, a peroxisome proliferator-activated receptor-␣ (PPAR-␣) agonist, increases protein expression of cytochrome P450 4A (CYP4A), which is responsible for 20-HETE synthesis in the kidney. Experiments were designed to determine whether clofibrate reduces hypertension associated with chronic ET B receptor blockade. Male Sprague-Dawley rats received either normal-salt (0.8% NaCl) or high-salt (8% NaCl) diet for 10 days. Female rats were fed a high-salt (8% NaCl) diet for 10 days. During the last 7 days, rats of both sexes were divided into 3 treatment groups: (1) [1][2][3] In the kidney, ET-1 is synthesized from a variety of cells such as vascular endothelium, mesangial cells, tubular epithelial cells, and medullary interstitium. 4 -10 The primary receptor subtype on renal tubular epithelial cells is the ET B receptor. 3 Studies have demonstrated that ET-1 stimulates sodium and water excretion through ET B receptor activation. 11 Consistent with a pronatriuretic function, our laboratory has shown that blocking ET B receptors causes salt-dependent hypertension along with elevated plasma ET-1 levels. 12,13 The latter effect is thought to be attributable to reduced clearance of ET-1 in the absence of ET B receptor availability.The role of cytochrome P450 (CYP450) hydroxylase metabolites in the maintenance of arterial pressure is complex because of their contrasting hypertensive and antihypertensive properties. 14 Clofibrate, a peroxisome proliferator activated receptor-␣ (PPAR-␣) agonist, has been shown to reduce arterial pressure in Dahl salt-sensitive rats on high salt diet by inducing the genes that code for CYP4504A (CYP4A) enzymes in the renal cortex. 15,16 CYP4A is the enzyme responsible for the synthesis of 20-HETE. Interestingly, 20-HETE has actions to reduce sodium transport and, like ET B receptor activation, has been implicated in saltdependent hypertension. [17][18][19][20][21] Previous studies have provided evidence that 20-HETE contributes to ET-1-mediated natriuretic responses. 22 Blockade of CYP4A and 20-HETE prevented the increase in urinary sodium excretion produced by ET-1. 23 Similarly, inhibition of 20-HETE formation in isolated proximal tubules prevented the blockade of ion transport produced by ET-1, indicating that 20-HETE acts as a second messenger of ET-1 in the proximal tubule. 23 Because the ET-1-mediated diuretic and natriuretic effects are through ET B activation, it is reasonable to presume that ET-1 stimulates 20-HETE formation through ET B receptors. The purpose of the present study was to determine the influence of PPAR-␣ activation and upregulation of CYP4A in the salt-sensitive hypertension produced by chronic ET B receptor blockade.

Nuclear Hormone Receptors as Regulators of the Renin-Angiotensin-Aldosterone System

“…17 The exact role of PPAR-␣ in the regulation of blood pressure remains unclear, because several other studies conducted in various rat models of hypertension have provided inconsistent results. 18,19 It is currently not known whether renin activation associated with PPAR-␣ activation is a direct transcriptional effect of PPAR-␣ or if it should be regarded as a secondary phenomenon, attributable to concomitant blood pressure reduction or other ancillary effects of PPAR agonists (eg, antiinflammatory and antiproliferative effects on the vasculature or increased sympathetic activity).…”

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

“…However, other PPAR-␣ agonists (ie, docosahexaenoic acid and clofibrate) have decreased BP in other models of hypertension, possibly by inhibiting NADPH oxidase-induced oxidative stress and inflammation in the vascular wall 29 and reducing endothelin-B receptor blockade in the kidney. 30 We previously showed that aldosterone increases myocyte MMP activity and extracellular signal-regulated kinase phosphorylation 11 and may be inhibited by fenofibrate. 19 Similar to other in vivo models of HF (ie, mice subjected to pressure overload or angiotensin II infusions), aldosterone administration induces a proinflammatory and a profibrotic phenotype.…”

Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier

“…Previous studies have indicated that increasing the renal formation of 20-HETE and/or EETs protects against the development of hypertension-induced proteinuria and glomerular disease (7,14,20,25,27,28) and that exogenous administration of 20-HETE opposes the effects of TGF-␤ and puromycin to increase P alb (4,12). The present results now extend these findings and indicate that glomeruli normally produce 20-HETE, EETs, diHETEs, and other HETEs and that the endogenous formation of both 20-HETE and EETs plays an essential role in the maintenance of the glomerular permeability barrier to albumin.…”